Formulations for the delivery of active ingredients

ABSTRACT

This invention relates generally to in vivo delivery of active ingredient formulations. More particularly, this invention relates to formulations of active ingredients that further comprise an agent, methods of making such formulations, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of U.S. application Ser. No.15/479,879, filed on Apr. 5, 2017, which is a continuation of U.S.application Ser. No. 14/399,235, filed on Nov. 6, 2014, now U.S. Pat.No. 9,700,624, issued on Jul. 11, 2017, which is a U.S. National Stageentry pursuant to 35 U.S.C. § 371 from International Application No.PCT/US2013/040426, filed on May 9, 2013, which claims the benefit ofpriority to U.S. Provisional Application No. 61/645,475, filed on May10, 2012, the contents of each of which are hereby incorporated byreference in their entireties for all purposes.

FIELD OF THE INVENTION

This invention relates generally to in vivo delivery of activeingredient formulations. More particularly, this invention relates toformulations of active ingredients that further comprise an in vivostabilizing amount of an agent, methods of making such formulations, andmethods of using the same.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith areincorporated herein by reference in their entirety: A computer readableformat copy of the Sequence Listing (filename: ADDY_002_03US_ST25.txt,date recorded: Aug. 27, 2019, file size 11.4 kilobytes).

BACKGROUND OF THE INVENTION

Active ingredients, such as drugs that contain peptides, proteins,nucleic acids, or small organic molecules, may cause unwanted effectsupon in vivo administration, such as to a mammal (e.g., a human). Sucheffects can detract significantly from the therapeutic benefit offeredby the active ingredient itself. Accordingly, a need exists forformulations of active ingredients that minimize unwanted effects of invivo administration.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the discovery thathomeostatic levels of certain agents are important with respect toadverse effect(s) of a therapeutic entity, e.g., an active ingredient ofa therapeutic entity. Accordingly the present invention providescompositions or formulations capable of inhibiting or reducing adverseeffect(s) of a therapeutic entity. In addition, the present inventionalso provides methods of using the composition or formulations fortherapeutic treatments.

In one embodiment, the present invention provides a composition, such asa pharmaceutical composition, comprising an active ingredient and an invivo stabilizing amount of an agent, wherein the agent is associatedwith an adverse effect in vivo caused by the administration of theactive ingredient without the agent, and wherein the in vivo stabilizingamount is the amount that substantially saturates the binding sites ofthe active ingredient to the agent.

In another embodiment, the present invention provides a method ofreducing an adverse effect of an active ingredient comprisingadministering the active ingredient with an in vivo stabilizing amountof an agent, wherein the agent is associated with the adverse effect ofthe active ingredient caused by the administration of the activeingredient without the agent, and wherein the in vivo stabilizing amountis the amount that substantially saturates the binding sites of theactive ingredient to the agent.

Further provided is a method for treating or managing pain in a subjectcomprising administering to the subject the pharmaceutical compositionas described herein, wherein the active ingredient is an oligonucleotidedecoy comprising one or more binding sites for EGR1 and wherein theagent is a calcium ion.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A, 1B, and 1C: clinical response scores of oligonucleotideformulations. FIG. 1A: the clinical response score of each testedformulation was calculated as the total sum of clinical signs anddisplayed in a graph bar (maximum potential score=13, minimum potentialscore=0). FIG. 1B and FIG. 1C present visual plots of the performance ofthe “saline+oligonucleotide” and the “1:0.0146 oligonucleotide:calcium”formulations, respectively. Each brown bar or surface on the plot marksthe % of occurrence of a given clinical sign. Oligonucleotide molecularweight=14092.92 g/mol, CaCl₂ molecular weight=147.02 g/mol,single-strand=antisense strand of the double stranded oligonucleotide,oligonucleotides were injected at 100 mg/mL, N=2-6 rats per formulation,T-test, different from saline injection: p<0.05.

FIG. 2: analysis of an oligonucleotide-calcium binding relationship.Oligonucleotide (0.05 mM to 3 mM) was incubated in presence of variousconcentrations of CaCl₂ (0.14 to 25 mM). Following incubation of CaCl₂and oligonucleotide, the amount of free calcium remaining in thesolution was measured using o-cresolphthalein, a dye binding to freecalcium (Calcium Colorimetric Assay Kit, BioVision). The quantity ofcalcium bound to the oligonucleotide was calculated as the differencebetween the calcium initially introduced in the solution minus the freecalcium remaining after incubation (30-60 min). The ratio ofconcentrations of calcium added in the solution divided by theoligonucleotide concentration was plotted against the concentration ofcalcium bound to the oligonucleotide divided by the oligonucleotideconcentration (circles). The relationship was linear: R²=0.89,slope=0.61, showing that the majority of the calcium was bound to theoligonucleotide. The same experiments were performed in presence of ahigher ionic strength by adding NaCl in 2 (triangles) or 12 (squares)fold excess of the calcium concentration. N=1-4 per condition, mean dataare presented, oligonucleotide molecular weight=14092.92 g/mol, CaCl₂molecular weight=147.02 g/mol.

FIG. 3: bar graphs representing free calcium in oligonucleotideformulations. The oligonucleotide was incubated with CaCl₂ at a molarratio of 1.8±0.3 up to the solubility limit of the oligonucleotide (13.5mM). Three formulations were tested with the following oligonucleotide:CaCl₂ concentrations (mM): 0.6:1.08, 7.8:14.04 and 13.5:24.3. After anincubation period of 30 min, free calcium was isolated usingultrafiltration centrifugal membranes (AMICON ULTRA 0.5 ML 3 KDA,Millipore) and its concentration measured using a calcium ion electrode(black bar). A similar experiment was conducted in conditions with ionicstrength comparable to cerebrospinal fluid (CSF) (138 mM NaCl, whitebar). The dashed bars represent the range of the endogenous level ofcalcium concentration in the CSF (1-1.4 mM). N=2 per condition,oligonucleotide molecular weight=14092.92 g/mol, CaCl₂ molecularweight=147.02 g/mol.

FIGS. 4A and 4B: oligonucleotide affinity and stability studies in thepresence of calcium. FIG. 4A is a bar graph illustrating oligonucleotidebinding affinity for its target, the transcription factor EGR1, asmeasured using a competition ELISA assay. A biotinylated EGR1 consensustandem oligonucleotide (12 pmoles) was bound to the ELISA plate andincubated with nuclear protein extracts containing EGR1 in absence(white bar) or presence (black bars) of 100 pmoles of free competitoroligonucleotide including various excess molar ratios of CaCl₂ (X=CaCl₂concentration/oligonucleotide concentration); FIG. 4B: oligonucleotide(4 μM) in the absence or presence of increasing excess molar ratios ofCaCl₂ (X=CaCl₂ concentration/oligonucleotide concentration) wasincubated in inactivated serum (Horse Serum, Heat Inactivated,Invitrogen) at 37° C. for 10 or 60 minutes. The quantity of intactoligonucleotide remaining following the incubation in the serum, whichcontains nucleases that degrade oligonucleotides, was measured using agel electrophoresis and UV detection method. Data were normalizedagainst the initial amount of oligonucleotide initially introduced inthe solution.

FIGS. 5A and 5B show the efficacy of a oligonucleotide for preventingpain in the spared nerve injury model of pain (Decosterd and Woolf, Pain87:149-158 (2000)). Vehicle (triangle) or oligonucleotide (circle) wereinjected intrathecally (percutaneous, L5/6, 0.02 mL) once at the time ofsurgery. Pain was measured as mechanical hypersensitivity using Von Freyfilaments (VF). Five repetitive applications for each of the followingVF hair were performed on the paw ipsilateral to injury: 1-4-6-8-10(twice)-26 gram. FIG. 5A: 1.4 mg of oligonucleotide without calcium vs.vehicle; FIG. 5B: 1.4 mg of oligonucleotide with CaCl₂ at the 1:0.0198weight ratio vs. vehicle and buffered at pH 7.5 with Tris 10 mM.Median±40% and 60% percentiles values of total responses to repetitiveVF stimulations are shown; N≥4 per group, T-test followed by a T-Welshanalysis, data distribution over the testing period, different fromvehicle; p<0.01 in both studies.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the discovery thathomeostatic levels of certain agents are important with respect toadverse effect(s) of a therapeutic entity, e.g., an active ingredient ofa therapeutic entity. Accordingly the present invention providescompositions or formulations capable of inhibiting or reducing adverseeffect(s) of a therapeutic entity. In addition, the present inventionalso provides methods of using the compositions or formulations fortherapeutic treatments.

In one aspect, the present invention provides a composition, such as apharmaceutical composition, comprising an active ingredient and an agentassociated, directly or indirectly, with one or more adverse effect(s)of the active ingredient. In one embodiment, the agent is any entity, ofwhich the homeostatic levels are directly or indirectly related to oneor more adverse effect(s) of the active ingredient. In anotherembodiment, the agent is any entity, of which the homeostatic levels arechanged, e.g., substantially upon administration of the activeingredient in vivo. In yet another embodiment, the agent is any entity,of which the homeostatic levels are sensitive to the administration ofthe active ingredient in vivo. In still another embodiment, the agent isany entity which is capable of interacting or interacts, directly orindirectly, with the active ingredient. In still yet another embodiment,the agent is any entity which is capable of binding or binds, directlyor indirectly, with the active ingredient.

According to the present invention, the agent can be different, e.g.,even with respect to the same active ingredient, depending on the tissueor cell type the active ingredient is administered into. In someembodiments, the agent is an ion. An ion can be an organic acid, such asmalic, ascorbic, tartaric, lactic, acetic, formic, oxalic, or citricacid. In some embodiments, the agent is a metal ion, e.g., iron, zinc,copper, lead and nickel, etc. In some embodiments, the agent has acharge that is opposite of the net charge of the active ingredient. Insome embodiments, the agent is a cation or anion. In some otherembodiments, the agent is a calcium ion, a magnesium ion, or a potassiumion. In some other embodiments, the agent is an ion, carbohydrate (e.g.,sugars, starches, etc.), lipid (e.g., saturated fatty acids, unsaturatedfatty acids, triacylglycerols, glycerophospholipids, sphingolipids, andcholesterol, etc.), vitamin (e.g., selenium, zinc, vitamin A, thiamine,riboflavin, pyridoxin, niacin, pantothenic acid, cyanocobalamin,L-ascorbic acid and α-tocopherol, etc.), or alcohol (e.g., polyols suchas glucose and mannitol, as well as, e.g., ethanol, etc.) or acombination thereof.

In yet further embodiments, the agent with respect to cerebrospinalfluid is an ion, e.g., calcium ions, magnesium ions or potassium ions.In still some other embodiments, the agent with respect to blood is oneor more blood electrolytes and/or major constituents of extracellular,cellular and interstitial fluids. In some exemplary embodiments, theagent with respect to blood is Na⁺, K⁺, Ca²⁺, Mg²⁺, Cl⁻, bicarbonates(e.g., HCO₃ ⁻ ), phosphorus (e.g., HPO₄ ²⁻), sulfates (e.g., SO₄ ²⁻),organic acid, proteins, metal ions (iron, zinc, copper, lead and nickel,etc.), carbohydrates or alcohols (e.g., glucose, mannitol, ethanol),lipids, vitamins (e.g., selenium, zinc) or any combination thereof.

According to the present invention, the agent used in the composition ofthe active ingredient can be any amount suitable for the administrationof the active ingredient in vivo, e.g., any amount that either inhibitsor decreases one or more adverse effect(s) of the active ingredientwithout the agent. According to the present invention, one or moreadverse effect(s) of the active ingredient includes any unwanted orundesirable effect produced as a result of in vivo administration of theactive ingredient. An adverse effect can be any long term or shorteffect, local or systematic effect, or any effect associated with thetoxicity of the active ingredient. Exemplary adverse effects includepain, headache, vomiting, arrhythmia, shivering, respiratory depression,dizziness, loss of motor control, lack of coordination, fatigue, memoryimpairment, rash, or numbness. In one embodiment, the adverse effect inthe context of pain treatment with an oligonucleotide decoy can berelatively minor (e.g., light tail movement in a rodent or dog animalmodel) or more severe (e.g., a seizure), or may include muscletrembling, increased muscle tone in a limb, whole body rigidity, pain,or spontaneous vocalization.

In one embodiment, the agent used in the composition of the activeingredient is an in vivo stabilizing amount. As used herein, an “in vivostabilizing amount” is an amount of the agent that upon administrationalong with the active ingredient does not cause any material ordetectable change of the endogenous level, e.g., homeostatic level ofthe agent in vivo. Alternatively an “in vivo stabilizing amount” is anamount of the agent that upon administration along with the activeingredient inhibits or decreases one or more adverse effect(s) of theactive ingredient without the agent. In some embodiments, the in vivostabilizing amount of the agent is an amount that sufficiently saturatesbinding sites, e.g., available binding sites of the active ingredient tothe agent. For example, the in vivo stabilizing amount of the agent canbe an amount that capable of binding or binds to at least 0.001%, 0.1%,0.5%, 1%, 2%, 5%, 10%, 20%, 30%, 40%, or 50% of binding sites, e.g.,available binding sites of the active ingredient to the agent. In someother embodiments, the in vivo stabilizing amount of the agent is anamount that upon administration along with the active ingredient doesnot materially affect or cause detectable change of the pH (e.g.,induces a change less than about 0.5 pH units, 0.2 pH units, 0.1 pHunits, etc.) of the local site, tissue, or cell environment, etc.

In yet some other embodiments, the in vivo stabilizing amount of theagent is the amount that upon mixing with the active ingredient producesless than a predetermined level of free agent in the composition, e.g.,minimum or undetectable level of free agent in the composition. Forexample, the predetermined level of free agent in the composition can beat least less than 0.1 mM, 0.5 mM, 1 mM, 1.5 mM, or 2 mM in acomposition when the active ingredient is an oligonucleotide decoy andthe agent is an ion, e.g., calcium. In another example, thepredetermined level of the free agent in the composition is less thanabout 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% ofthe endogenous level, e.g., local concentration of the agent. In yetanother example, the predetermined level of free agent in thecomposition is determined based on the saturation level of the bindingsites in the active ingredient to the agent.

According to the present invention, the free agent is the agent that isnot bound to the active ingredient, e.g., by electrostatic, covalent, orhydrophobic interactions, or any other mode of interaction.Alternatively the free agent is the agent that is capable of interferingor interferes with the endogenous level of the agent, e.g.,systematically or at the local site of administration.

In still some other embodiments, the in vivo stabilizing amount of theagent is the amount that provide suitable ratio between the activeingredient and the agent so that when they are administered in vivo, itinhibits or decreases one or more adverse effect(s) of the activeingredient without the agent or alternatively it does not causesubstantial or detectable change of endogenous level, e.g., homeostaticlevel of the agent. In some embodiments, the molar ratio or the weightratio of the active ingredient to the agent ranges from about 1:1000 toabout 1000:1. Non-limiting examples of ratios include 1:1, 1:5, 1:10,1:50, 1:100, 1:250, 1:500, 1:1000, 1000:1, 500:1, 250:1, 100:1, 50:1,10:1, 5:1, and any range derivable therein inclusive of fractions ofintegers (e.g., 100.5, 100.05, etc.). Further non-limiting examples ofratios include 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 10:1,9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, and 2:1, and any range derivabletherein, inclusive of fractions of integers (e.g., 1.5, 1.05, etc.). Insome embodiments, the active ingredient is a nucleic acid, such as anoligonucleotide (e.g., an oligonucleotide decoy), and the agent is acalcium ion, and wherein the weight ratio or the molar ratio of theactive ingredient and the agent is from about 0.005 to 5, 0.05 to 5, 0.1to 3, 0.2 to 2.8, 0.5 to 2, or 1 to 2. In some embodiments, the activeingredient is a nucleic acid, such as an oligonucleotide (e.g., anoligonucleotide decoy), and the agent is a calcium ion, and wherein theweight ratio or the molar ratio of the active ingredient and the agentis from about 1 to 0.001, 1 to 0.005, 1 to 0.01, 1 to 0.015, 1 to 0.018,1 to 0.019, 1 to 0.02, 1 to 0.025, 1 to 0.03, 1 to 0.035, 1 to 0.4, or 1to 0.5. For example, the weight ratio may be 1:1, 2:1, 4:1, 5:1, 15:1,30:1, 50:1, 100:1, 200:1, 250:1, 300:1, 400:1, 500:1, or 1000:1. Anagent, such as an ion (e.g., a calcium ion), can be comprised in acomposition such as a salt (e.g., CaCl₂), and the molar amount or weightamount of that composition can be referenced in a ratio. Accordingly, insome embodiments, the agent is a calcium ion comprised in a compositionsuch as CaCl₂, wherein the weight ratio of an active ingredient, such asa nucleic acid (e.g., an oligonucleotide, an oligonucleotide decoy) tothe composition, e.g., CaCl₂, is about 1:1, 2:1, 4:1, 5:1, 15:1, 30:1,50:1, 100:1, 200:1, 250:1, 300:1, 400:1, or 500:1, or any rangederivable therein.

It is understood that the exact ratio of active ingredient to agent in acomposition may vary, such as based on the chemical nature of the activeingredient (e.g., in the context of a nucleic acid, whether the nucleicacid is RNA, DNA, single stranded or double stranded, the percent GCcontent, or molecular weight), the agent and its local concentration(e.g., endogenous level) in the targeted in vivo site, and its intendeddelivery route. For example, in a environment with a higher endogenouscalcium concentration, it is anticipated that the ratio of activeingredient (e.g., oligonucleotide decoy):calcium should be increased ina composition comprising such components.

In still yet some other embodiments, the in vivo stabilizing amount ofthe agent is the amount that when administered along with the activeingredient causes minimum, insubstantial, or undetectable amount ofinteraction, e.g., binding between the endogenous agent and the activeingredient.

According to the present invention, the active ingredient is any entitywithin a composition that provides intended activity of the composition.In some embodiments, the active ingredient is any therapeutically,prophylactically, or pharmacologically or physiologically activesubstance, or a mixture thereof. In general, an active ingredient istypically used in an amount sufficient to prevent, cure, diagnose ortreat a disease or other condition, as the case may be. Non-limitingexamples of active ingredients include nucleic acids, peptides, andsmall organic molecules. As used herein, a “small organic molecule”refers to a carbon-containing agent having a molecular weight of lessthan or equal to 1500 g/mol, such less than 1400, less than 1300, lessthan 1200, less than 1100, less than 1000, less than 900, less than 800,less than 700, less than 600, less than 500, less than 400, less than300, less than 200, or less than 100 g/mol. In some embodiments, a smallorganic molecule excludes a polymer, such as a nucleic acid polymer(e.g., an oligonucleotide, polynucleotide, vector, etc.), a peptide, ora protein. In some embodiments, an active ingredient is a polymer, suchas a nucleic acid polymer or a protein.

In some other embodiments, an active ingredient is an oligonucleotide.For example, an oligonucleotide can be an oligonucleotide decoy, such asdescribed in U.S. Pat. Nos. 7,943,591 and 8,093,225. An “oligonucleotidedecoy” refers to any double-stranded, nucleic acid-containing polymergenerally less than approximately 200 nucleotides (or 100 base pairs)and including, but not limited to, DNA, RNA and RNA-DNA hybrids. Theterm encompasses sequences that include any of the known base analogs ofDNA and RNA including, but not limited to, 2,6-diaminopurine,5-carboxymethylaminomethyl-2-thiouracil,5-carboxymethylaminomethyluracil, dihydrouracil, inosine,uracil-5-oxyacetic acid, N6-isopentenyladenine, 1-methyladenine,N-uracil-5-oxyacetic acid methylester, queosine, 2-thiocytosine,5-bromouracil, methylphosphonate, phosphorodithioate, ormacetal,3′-thioformacetal, nitroxide backbone, sulfone, sulfamate, morpholinoderivatives, locked nucleic acid (LNA) derivatives, or peptide nucleicacid (PNA) derivatives. In some embodiments, the oligonucleotide decoyis composed of two complementary single-stranded oligonucleotides thatare annealed together. In other embodiments, the oligonucleotide decoyis composed of one single-stranded oligonucleotide that formsintramolecular base pairs to create a substantially double-strandedstructure.

In certain embodiments, the oligonucleotide decoys comprise one or more(e.g., 1, 2, 3, 4, 5, etc.) transcription factor binding sites. Inrelated embodiments, each transcription factor binding site binds to atranscription factor selected from the group consisting of POU1F1,POU2F, POU3F, POU4F1, POU5F1, USF, EGR1, CREB/ATF, AP1, CEBP, SRF, ETS1,MEF2, SP1, RUNX, NFAT, ELK1, ternary complex factors, STAT, GATA1, ELF1,nuclear factor—granulocyte/macrophage a, HNF1, ZFHX3, IRF, TEAD1, TBP,NFY, caccc-box binding factors, KLF4, KLF7, IKZF, MAF, REST, HSF, KCNIP3and PPAR transcription factors. In certain embodiments, transcriptionfactor binding sites bind to two or more members of a family ofclosely-related transcription factors. Representative members of suchtranscription factor families can be selected from the group consistingof POU1F1, POU2F, POU3F, POU4F1, POU5F1, USF, EGR1, CREB/ATF, AP1, CEBP,SRF, ETS1, MEF2, SP1, RUNX, NFAT, ELK1, ternary complex factors, STAT,GATA1, ELF1, nuclear factor—granulocyte/macrophage a, HNF1, ZFHX3, IRF,TEAD1, TBP, NFY, caccc-box binding factors, KLF4, KLF7, IKZF, MAF, REST,HSF, KCNIP3 and PPAR transcription factors. Thus, in certainembodiments, an oligonucleotide decoy that binds to, e.g., EGR1, canalso bind to one or more additional family members, e.g., EGR2, EGR3,EGR4.

In certain embodiments, the oligonucleotide decoys comprise two or more(e.g., 2, 3, 4, 5, etc.) transcription factor binding sites. In relatedembodiments, each transcription factor binding site binds to atranscription factor selected from the group consisting of POU1F1,POU2F, POU3F, POU4F1, POU5F1, USF, EGR1, CREB/ATF, AP1, CEBP, SRF, ETS1,MEF2, SP1, RUNX, NFAT, ELK1, ternary complex factors, STAT, GATA1, ELF1,nuclear factor—granulocyte/macrophage a, HNF1, ZFHX3, IRF, TEAD1, TBP,NFY, caccc-box binding factors, KLF4, KLF7, IKZF, MAF, REST, HSF, KCNIP3and PPAR transcription factors. In certain embodiments, the relativeposition of the two or more transcription factor binding sites withinthe decoy modulates (e.g., increases or decreases) the binding affinitybetween a target transcription factor (i.e., the transcription factorthat a particular binding site is designed to bind to) and itstranscription factor binding site, e.g., as compared to the bindingaffinity between the transcription factor and a decoy having a singletranscription factor binding site (e.g., a consensus binding site)specific to the transcription factor. Thus, the relative position of thetwo transcription factor binding sites within an oligonucleotide decoyof the invention can increase the affinity of the oligonucleotide decoyfor a target transcription factor (e.g., for one or more of thetranscription factors targeted by the decoy). In certain embodiments,the increase in affinity of the oligonucleotide decoy for a targettranscription factor is 1.2 fold or greater (e.g., about 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,2.9, 3.0 fold, or more). In certain embodiments, the relative positionof the two transcription factor binding sites within an oligonucleotidedecoy promotes protein-protein interactions between transcriptionfactors bound to the sites, e.g., homodimerization or heterodimerizationof the transcription factors. In certain embodiments, suchprotein-protein interactions between transcription factors stabilizetheir interactions, e.g., binding, to the oligonucleotide decoy, therebyincreasing the binding affinity of the oligonucleotide decoy for one ormore of the target transcription factors.

In certain embodiments, the transcription factor binding sites of anoligonucleotide decoy each bind to the same transcription factor, e.g.,EGR1. In other embodiments, the transcription factor binding sites of anoligonucleotide decoy bind to different transcription factors, e.g.,different members of a closely related family of transcription factors(e.g., different members of the EGR1 family) or a combination oftranscription factors selected from the group consisting of POU1F1,POU2F, POU3F, POU4F1, POU5F1, USF, EGR1, CREB/ATF, AP1, CEBP, SRF, ETS1,MEF2, SP1, RUNX, NFAT, ELK1, ternary complex factors, STAT, GATA1, ELF1,nuclear factor—granulocyte/macrophage a, HNF1, ZFHX3, IRF, TEAD1, TBP,NFY, caccc-box binding factors, KLF4, KLF7, IKZF, MAF, REST, HSF, KCNIP3and PPAR transcription factors.

In certain embodiments, the transcription factor binding sites of anoligonucleotide decoy are separated from each other by a linkersequence. Linker sequences can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or morebase pairs in length. Typically, linker sequences will be two to fivebase pairs in length. In other embodiments, the transcription factorbinding sites can be immediately adjacent to one another (e.g., nolinker sequence is present) or overlapping. In cases where thetranscription factor binding sites are overlapping, the transcriptionfactor binding sites can share 1, 2, 3, 4, 5, or more base pairs.Alternatively, one or both of the transcription factor binding sites canbe lacking base pairs that otherwise form part of a consensus bindingsequence for the transcription factor(s) that bind to the site. Ingeneral, however, base pairs that are critical to the bindinginteraction between a transcription factor binding site and thetranscription factors that bind to the site (e.g., base pairs that areessentially invariant in a consensus binding sequence for a particulartranscription factor) are not shared or missing when transcriptionbinding sequences are overlapping.

In certain embodiments, oligonucleotide decoys comprise flankingsequences located at each end of the decoy sequence. Flanking sequencescan be 1, 2, 3, 4, 5, 6, or more base pairs in length. In general,flanking sequences are two to five base pairs in length. In preferredembodiments, 5′ flanking sequences starts with a G/C base pair and 3′flanking sequences terminate in a G/C base pair. In preferredembodiments, flanking sequences do not form part of a transcriptionfactor binding site or do not interact with or bind to transcriptionfactors. In other embodiments, flanking sequences form weak interactionswith transcription factors bound to an adjacent transcription factorbinding site.

In certain embodiments, oligonucleotide decoys are generally at least10, 11, 12, 13, 14, 15, or more base pairs in length. In relatedembodiments, oligonucleotide decoys are generally less than 65, 60, 55,50, or 45 base pairs in length. In preferred embodiments,oligonucleotide decoys are about 20 to 40 base pairs in length. In otherembodiments, oligonucleotide decoys are about 20 to 35, 25 to 40, or 25to 35 base pairs in length.

In certain embodiments, the oligonucleotide decoys comprise: (a) asequence selected from the group consisting of SEQ ID NOs.: 1-40, 42, 45and 47-53; or (b) a sequence having at least 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% identity with a sequence selected from the group consisting of SEQID NOs.: 1-40, 42, 45 and 47-53. In related embodiments, theoligonucleotide decoys comprise a sequence having at least 90% identitywith a sequence selected from the group consisting of SEQ ID NOs.: 1-39,42, 45 and 47-52. In other embodiments, the oligonucleotide decoyscomprise a sequence having at least 85% identity with a sequenceselected from the group consisting of SEQ ID NOs.: 1-17, 19-39, 42, 45and 47-53. In other embodiments, the oligonucleotide decoys comprise asequence having at least 80% identity with a sequence selected from thegroup consisting of SEQ ID NOs.: 1-5, 7-17, 19-39, 42, 45 and 47-53. Inother embodiments, the oligonucleotide decoys comprise a sequence havingat least 75% identity with a sequence selected from the group consistingof SEQ ID NOs.: 1-4, 7-9, 13, 15-17, 19-23, 26-39, 45, 48, 50, 51 and53. In other embodiments, the oligonucleotide decoys comprise a sequencehaving at least 70% identity with a sequence selected from the groupconsisting of SEQ ID NOs.: 1-3, 7-9, 13, 15-17, 19-23, 26, 28, 30, 32,34-36, 38-39 and 48. In other embodiments, the oligonucleotide decoyscomprise a sequence having at least 65% identity with a sequenceselected from the group consisting of SEQ ID NOs.: 2-3, 9, 13, 15-16,19-23, 26, 28, 30, 32, 34-36, 38 and 39. In other embodiments, theoligonucleotide decoys comprise a sequence having at least 60% identitywith a sequence selected from the group consisting of SEQ ID NOs.: 2,13, 15-16, 21, 23, 26, 30, 32, 34-36, 38 and 39. In still otherembodiments, the oligonucleotide decoys comprise a sequence having atleast 55% identity with a sequence selected from the group consisting ofSEQ ID NOs.: 16, 23, 30, 32, 34, 35, 38 and 39. In still otherembodiments, the oligonucleotide decoys comprise a sequence having atleast 50% identity with a sequence selected from the group consisting ofSEQ ID NOs.: 30, 32, 35, and 38.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (1):

5′-S₁n₂n₃n₄n₅A₆T₇D₈B₉N₁₀d₁₁d₁₂n₁₃n₁₄n₁₅n₁₆n₁₇A₁₈T₁₉D₂₀ . . .B₂₁N₂₂H₂₃H₂₄n₂₅n₂₆n₂₇n₂₈n₂₉n₃₀S₃₁−3′  (1)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “D” can be an A, G, or Tnucleotide, “B” can be a C, G, or T nucleotide, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (1) hasat least about 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence ofSEQ ID NO.: 1. Such oligonucleotide decoys can bind to POU2F1transcription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toPOU2F1 transcription factor, such as POU2F2, POU3F1-2, and POU5F1.

In certain embodiments, an oligonucleotide decoy represented by formula(1) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, or 7)nucleotides selected from the group consisting of d₁₁, d₁₂, n₁₃, n₁₄,n₁₅, n₁₆, and n₁₇. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of d₁₁, d₁₂, n₁₃, n₁₄, n₁₅, n₁₆, and n₁₇ have at least 70%identity to the nucleotide sequence of SEQ ID NO.: 1.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (2):

5′-S₁n₂n₃n₄n₅n₆Y₇C₈V₉Y₁₀R₁₁N₁₂G₁₃n₁₄n₁₅c₁₆v₁₇y₁₈d₁₉b₂₀ . . .g₂₁y₂₂C₂₃V₂₄Y₂₅R₂₆B₂₇G₂₈R₂₉n₃₀n₃₁n₃₂n₃₃n₃₄n₃₅S₃₆-3   (2)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “D” can be an A, G, or Tnucleotide, “B” can be a C, G, or T nucleotide, “R” can be a G or an A,“V” can be an A, C, or G, “Y” can be a C or a T, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (2) hasat least about 60%, 65%,70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotidesequence of SEQ ID NO.: 2. Such oligonucleotide decoys can bind to USF1transcription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toUSF1 transcription factor, such as USF2.

In certain embodiments, an oligonucleotide decoy represented by formula(2) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or9) nucleotides selected from the group consisting of n₁₄, n₁₅, c₁₆, v₁₇,y₁₈, d₁₉, b₂₀, g₂₁, and y₂₂. In certain embodiments, oligonucleotidedecoys comprising a deletion of one or more nucleotides selected fromthe group consisting of n₁₄, n₁₅, c₁₆, v₁₇, y₁₈, d₁₉, b₂₀, g₂₁, and y₂₂have at least 60% identity to the nucleotide sequence of SEQ ID NO.: 2.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (3):

5′S₁n₂n₃W₄W₅G₆S₇G₈K₉R₁₀G₁₁G₁₂M₁₃n₁₄n₁₅n₁₆w₁₇w₁₈w₁₉g₂₀ . . .s₂₁g₂₂K₂₃R₂₄G₂₅G₂₆M₂₇D₂₈n₂₉n₃₀n₃₁n₃₂n₃₃S₃₄-3′  (3)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, ‘W’ can be an A or a T, “D” canbe an A, G, or T nucleotide, “R” can be a G or an A, “K” can be a T or aG, “M” can be a C or an A, lower case letters can optionally be deleted,and the numbers in subscript represent the position of a nucleotide inthe sequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (3) has at least about 65%, 70%, 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to the nucleotide sequence of SEQ ID NO.: 3. Sucholigonucleotide decoys can bind to EGR1 transcription factor. In certainembodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to EGR1 transcription factor, suchas EGR2-4.

In certain embodiments, an oligonucleotide decoy represented by formula(3) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or9) nucleotides selected from the group consisting of n₁₄, n₁₅, n₁₆, w₁₇,w₁₈, w₁₉, g₂₀, s₂₁, and g₂₂. In certain embodiments, oligonucleotidedecoys comprising a deletion of one or more nucleotides selected fromthe group consisting of n₁₄, n₁₅, n₁₆, w₁₇, w₁₈, w₁₉, g₂₀, s₂₁, and g₂₂have at least 65% identity to the nucleotide sequence of SEQ ID NO.: 3.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (4):

5′-S₁n₂n₃n₄n₅n₆n₇T₈K₉A₁₀S₁₁S₁₂b₁₃m₁₄n₁₅n₁₆T₁₇K₁₈A₁₉S₂₀ . . .S₂₁B₂₂M₂₃N₂₄n₂₅n₂₆n₂₇n₂₈S₂₉-3′  (4)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “B” can be a C,G or T, “K” canbe a T or a G, “M” can be a C or an A, lower case letters can optionallybe deleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (4) has at least about 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to the nucleotide sequence of SEQ ID NO.: 4. Sucholigonucleotide decoys can bind to CREB1 transcription factor. Incertain embodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to CREB1 transcription factor,such as CREB3-5 and ATF1-7.

In certain embodiments, an oligonucleotide decoy represented by formula(4) comprises a deletion of one or more (e.g., 1, 2, 3 or 4) nucleotidesselected from the group consisting of b₁₃,m₁₄,n₁₅, and n₁₆. In certainembodiments, oligonucleotide decoys comprising a deletion of one or morenucleotides selected from the group consisting of b₁₃,m₁₄,n₁₅, and n₁₆have at least 75% identity to the nucleotide sequence of SEQ ID NO.: 4.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (5):

5′-S₁S₂n₃n₄n₅n₆T₇G₈A₉S₁₀k₁₁n₁₂h₁₃r₁₄r₁₅r₁₆t₁₇G₁₈A₁₉S₂₀ . . .K₂₁N₂₂H₂₃r₂₄r₂₅n₂₆n₂₇n₂₈S₂₉S₃₀-3′  (5)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “R” can be a G or an A, “K” canbe a T or a G, “H” can be a C, T or an A, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (5) hasat least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO.:5. Such oligonucleotide decoys can bind to AP1/JUN transcriptionfactors. In certain embodiments, such oligonucleotide decoys can bind toone or more transcription factors closely related to AP1/JUNtranscription factors, such as AP1/JUN-B, -D and AP1/FOS.

In certain embodiments, an oligonucleotide decoy represented by formula(5) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5 , 6 or 7)nucleotides selected from the group consisting of k₁₁, n₁₂, h₁₃, r₁₄,r₁₅, r₁₆, and t₁₇. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of k₁₁, n₁₂, h₁₃, r₁₄, r₁₅, r₁₆, and t₁₇ have at least 80%identity to the nucleotide sequence of SEQ ID NO.: 5.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (6):

5′-S₁n₂n₃n₄n₅w₆w₇w₈G₉A₁₀T₁₁T₁₂K₁₃T₁₄s₁₅s₁₆a₁₇a₁₈k₁₉s₂₀ . . .n₂₁g₂₂A₂₃T₂₄T₂₅K₂₆T₂₇C₂₈S₂₉A₃₀A₃₁K₃₂S₃₃n₃₄n₃₅n₃₆S₃₇-3′  (6)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be A or T, “K” can be aT or a G, lower case letters can optionally be deleted, and the numbersin subscript represent the position of a nucleotide in the sequence.Although the formula shows a single strand, it should be understood thata complementary strand is included as part of the structure. Inpreferred embodiments, an oligonucleotide decoy having a sequencerepresented by formula (6) has at least about 85%, 88%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotidesequence of SEQ ID NO.: 6. Such oligonucleotide decoys can bind to CEBPAtranscription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toCEBPA transcription factor, such as CEBP-B, -D, -E, -G, -Z.

In certain embodiments, an oligonucleotide decoy represented by formula(6) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or 8)nucleotides selected from the group consisting of s₁₅, s₁₆, a₁₇, a₁₈,k₁₉, s₂₀,n₂₁, and g₂₂. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of s₁₅, s₁₆, a₁₇, a₁₈, k₁₉, s₂₀, n₂₁, and g₂₂ have at least85% identity to the nucleotide sequence of SEQ ID NO.: 6.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (7):

5′-S₁n₂n₃n₄n₅n₆g₇g₈a₉t₁₀r₁₁t₁₂C₁₃C₁₄A₁₅T₁₆A₁₇T₁₈T₁₉A₂₀ . . .G₂₁G₂₂a₂₃g₂₄a₂₅t₂₆n₂₇n₂₈n₂₉n₃₀w₃₁w₃₂s₃₃S₃₄-3′  (7)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or T, Y can bea C or T, “R” can be a G or A, lower case letters can optionally bedeleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (7) has at least about 70%,75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to the nucleotide sequence of SEQ ID NO.: 7. Sucholigonucleotide decoys can bind to SRF transcription factor. In certainembodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to SRF transcription factor, suchas ELK1.

In certain embodiments, an oligonucleotide decoy represented by formula(7) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16 or 17) nucleotides selected from the groupconsisting of g₈, g₈, a₉, t₁₀, r₁₁, t₁₂, a₂₃, g₂₄, a₂₅, t₂₆, n₂₇, n₂₈,n₂₉, n₃₀, w₃₁, w₃₂ and s₃₃. In certain embodiments, oligonucleotidedecoys comprising a deletion of one or more nucleotides selected fromthe group consisting of g₇, g₈, a₉, t₁₀, r₁₁, t₁₂, a₂₃, g₂₄, a₂₅, t₂₆,n₂₇,n₂₈,n₂₉,n₃₀,w₃₁,w₃₂ and s₃₃ have at least 70% identity to thenucleotide sequence of SEQ ID NO.: 7.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (8):

5′-S₁n₂n₃n₄n₅C₆A₇G₈G₉A₁₀d₁₁d₁₂d₁₃d₁₄d₁₅d₁₆d₁₇d₁₈d₁₉T₂₀ . . .C₂₁C₂₂A₂₃T₂₄A₂₅T₂₆T₂₇A₂₈G₂₉n₃₀n₃₁n₃₂n₃₃S₃₄-3′  (8)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “D” can be an A, T or G, lowercase letters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (8) has at least about 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotidesequence of SEQ ID NO.: 8. Such oligonucleotide decoys can bind to SRFtranscription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toSRF transcription factor, such as ETS1.

In certain embodiments, an oligonucleotide decoy represented by formula(8) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or9) nucleotides selected from the group consisting of d₁₁, d₁₂, d₁₃, d₁₄,d₁₅, d₁₆, d₁₇, d₁₈ and d₁₉. In certain embodiments, oligonucleotidedecoys comprising a deletion of one or more nucleotides selected fromthe group consisting of d₁₁, d₁₂, d₁₃, d₁₄, d₁₅, d₁₆, d₁₇, d₁₈ and d₁₉have at least 70% identity to the nucleotide sequence of SEQ ID NO.: 8.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (9):

5′-S₁n₂n₃n₄n₅C₆T₇A₈W₉A₁₀M₁₁W₁₂T₁₃A₁₄A₁₅n₁₆n₁₇n₁₈n₁₉c₂₀ . . .t₂₁A₂₂W₂₃A₂₄A₂₅A₂₆T₂₇A₂₈A₂₉A₃₀A₃₁n₃₂n₃₃n₃₄S₃₅-3′  (9)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or an T, “M”can be a C or an A, lower case letters can optionally be deleted, andthe numbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (9) has at least about 65%, 70%, 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to the nucleotide sequence of SEQ ID NO.: 9. Sucholigonucleotide decoys can bind to MEF2A transcription factor. Incertain embodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to MEF2A transcription factor,such as MEF2B-C.

In certain embodiments, an oligonucleotide decoy represented by formula(9) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5 or 6)nucleotides selected from the group consisting of n₁₆, n₁₇, n₁₈, n₁₉,c₂₀ and t₂₁. In certain embodiments, oligonucleotide decoys comprising adeletion of one or more nucleotides selected from the group consistingof n₁₆, n₁₇, n₁₈, n₁₉, c₂₀ and t₂₁ have at least 65% identity to thenucleotide sequence of SEQ ID NO.: 9.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (10):

5′-n₁n₂n₃n₄R₅R₆G₇S₈C₉S₁₀K₁₁r₁₂r₁₃n₁₄n₁₅n₁₆r₁₇r₁₈G₁₉S₂₀ . . .C₂₁K₂₂R₂₃R₂₄N₂₅n₂₆n₂₇n₂₈n₂₉n₃₀-3′  (10)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “K” can be a T or a G, “R” canbe a G or an A, lower case letters can optionally be deleted, and thenumbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (10) has at least about 80%, 85%, 88%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity tothe nucleotide sequence of SEQ ID NO.: 10. Such oligonucleotide decoyscan bind to SP1 transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to SP1 transcription factor, such as SP2-8.

In certain embodiments, an oligonucleotide decoy represented by formula(10) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6 or 7)nucleotides selected from the group consisting of r₁₂, r₁₃, n₁₄, n₁₅,n₁₆, r₁₇, and r₁₈. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of n₁₆, n₁₇, n₁₈, n₁₉, c₂₀ and t₂₁ have at least 80% identityto the nucleotide sequence of SEQ ID NO.: 10.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (11):

5′-n₁n₂n₃n₄n₅G₆G₇C₈G₉G₁₀G₁₁G₁₂s₁₃s₁₄s₁₅s₁₆s₁₇s₁₈s₁₉s₂₀ . . .s₂₁s₂₂s₂₃C₂₄G₂₅G₂₆G₂₇C₂₈G₂₉G₃₀T₃₁T₃₂T₃₃A₃₄C₃₅-3′  (11)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (11) hasat least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO.:11. Such oligonucleotide decoys can bind to SP1 transcription factor. Incertain embodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to SP1 transcription factor, suchas SP2-8.

In certain embodiments, an oligonucleotide decoy represented by formula(11) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6 , 7, 8,9, 10 or 11) nucleotides selected from the group consisting of s₁₃, s₁₄,s₁₅, s₁₆, s₁₇, s₁₈, s₁₉, s₂₀, s₂₁, s₂₂, and s₂₃. In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of s₁₃, s₁₄, s₁₅, s₁₆, s₁₇, s₁₈, s₁₉,s₂₀, s₂₁, s₂₂, and s₂₃ have at least 80% identity to the nucleotidesequence of SEQ ID NO.: 11.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (12):

5′-S₁n₂n₃n₄n₅W₆G₇Y₈G₉G₁₀t₁₁d₁₂d₁₃d₁₄d₁₅g₁₆W₁₇G₁₈Y₁₉G₂₀ . . .G₂₁T₂₂D₂₃D₂₄D₂₅D₂₆n₂₇n₂₈S₂₉-3′  (12)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, Y canbe a C or a T, “D” can be an A, T or a G, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (12) hasat least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO.:12. Such oligonucleotide decoys can bind to RUNX1 transcription factor.In certain embodiments, such oligonucleotide decoys can bind to one ormore transcription factors closely related to RUNX1 transcriptionfactor, such as RUNX2-3.

In certain embodiments, an oligonucleotide decoy represented by formula(12) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5 or 6)nucleotides selected from the group consisting of t₁₁, h₁₂, h₁₃, h₁₄,h₁₅, and g₁₆. In certain embodiments, oligonucleotide decoys comprisinga deletion of one or more nucleotides selected from the group consistingof t₁₁, h₁₂, h₁₃, h₁₄, h₁₅, and g₁₆ have at least 80% identity to thenucleotide sequence of SEQ ID NO.: 12.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (13):

5′-S₁n₂n₃n₄n₅T₆T₇G₈G₉G₁₀G₁₁T₁₂C₁₃A₁₄T₁₅A₁₆n₁₇n₁₈n₁₉n₂₀ . . .C₂₁A₂₂C₂₃A₂₄G₂₅G₂₆A₂₇A₂₈C₂₉C₃₀A₃₁C₃₂A₃₃n₃₄n₃₅S₃₆-3′  (13)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (13) hasat least about 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotidesequence of SEQ ID NO.: 13. Such oligonucleotide decoys can bind toRUNX1 transcription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toRUNX1 transcription factor, such as RUNX2-3.

In certain embodiments, an oligonucleotide decoy represented by formula(13) comprises a deletion of one or more (e.g., 1, 2, 3 or 4)nucleotides selected from the group consisting of n₁₇, n₁₈, n₁₉ and n₂₀.In certain embodiments, oligonucleotide decoys comprising a deletion ofone or more nucleotides selected from the group consisting of n₁₇, n₁₈,n₁₉ and n₂₀ have at least 60% identity to the nucleotide sequence of SEQID NO.: 13.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (14):

5′-S₁n₂n₃n₄n₅n₆C₇H₈G₉G₁₀A₁₁H₁₂R₁₃y₁₄n₁₅n₁₆n₁₇c₁₈C₁₉G₂₀ . . .G₂₁A₂₂H₂₃R₂₄Y₂₅n₂₆n₂₇n₂₈n₂₉n₃₀n₃₁S₃₂-3′  (14)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “R” can be G or A, “H” can beA, T or C, “Y” can be a C or a T, lower case letters can optionally bedeleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (14) has at least about 80%,85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity to the nucleotide sequence of SEQ ID NO.: 14. Sucholigonucleotide decoys can bind to ETS1 transcription factor. In certainembodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to ETS1 transcription factor, suchas ELK1.

In certain embodiments, an oligonucleotide decoy represented by formula(14) comprises a deletion of one or more (e.g., 1, 2, 3, 4 or 5)nucleotides selected from the group consisting of y₁₄, n₁₅, n₁₆, n₁₇ andc₁₈. In certain embodiments, oligonucleotide decoys comprising adeletion of one or more nucleotides selected from the group consistingof y₁₄, n₁₅, n₁₆, n₁₇ and c₁₈ have at least 80% identity to thenucleotide sequence of SEQ ID NO.: 14.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (15):

5′-S₁n₂n₃M₄W₅W₆G₇G₈A₉A₁₀A₁₁A₁₂n₁₃n₁₄d₁₅w₁₆w₁₇g₁₈g₁₉a₂₀ . . .a₂₁a₂₂a₂₃n₂₄n₂₅d₂₆w₂₇G₂₈G₂₉A₃₀A₃₁A₃₂A₃₃n₃₄n₃₅n₃₆n₃₇n₃₈n₃₉S₄₀-3′  (15)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “D” can be an A,G or a T, “W”can be an A or a T, “M” can be C or A, lower case letters can optionallybe deleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (15) has at least about 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO.:15. Such oligonucleotide decoys can bind to NFATC1 transcription factor.In certain embodiments, such oligonucleotide decoys can bind to one ormore transcription factors closely related to NFATC1 transcriptionfactor, such as NFATC2-4.

In certain embodiments, an oligonucleotide decoy represented by formula(15) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14 or 15) nucleotides selected from the groupconsisting of n₁₃, n₁₄, d₁₅, w₁₆, w₁₇, g₁₈, g₁₉, a₂₀, a₂₁, a₂₂, a₂₃,n₂₄, n₂₅, d₂₆ and w₂₇. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of n₁₃, n₁₄, d₁₅, w₁₆, w₁₇, g₁₈, g₁₉, a₂₀, a₂₁, a₂₂, a₂₃,n₂₄, n₂₅, d₂₆ and w₂₇ have at least 60% identity to the nucleotidesequence of SEQ ID NO.: 15.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (16):

5′-S₁n₂n₃n₄n₅n₆C₇A₈C₉T₁₀T₁₁C₁₂C₁₃y₁₄v₁₅m₁₆n₁₇n₁₈n₁₉y₂₀ . . .v₂₁C₂₂T₂₃T₂₄C₂₅C₂₆T₂₇G₂₈C₂₉n₃₀n₃₁n₃₂S₃₃-3′  (16)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “V” can beG, A or C, “M” can be C or A, lower case letters can optionally bedeleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (16) has at least about 55%,60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% sequence identity to the nucleotide sequence of SEQ IDNO.: 16. Such oligonucleotide decoys can bind to ELK1 transcriptionfactor. In certain embodiments, such oligonucleotide decoys can bind toone or more transcription factors closely related to ELK1 transcriptionfactor, such as ETS1.

In certain embodiments, an oligonucleotide decoy represented by formula(16) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or8) nucleotides selected from the group consisting of y₁₄, v₁₅, m₁₆, n₁₇,n₁₈, n₁₉, y₂₀ and v₂₁. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of y₁₄, v₁₅, m₁₆, n₁₇, n₁₈, n₁₉, y₂₀ and v₂₁ have at least55% identity to the nucleotide sequence of SEQ ID NO.: 16.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (17):

5′-S₁n₂n₃n₄n₅n₆C₇T₈A₉T₁₀A₁₁A₁₂A₁₃T₁₄g₁₅g₁₆c₁₇c₁₈t₁₉A₂₀ . . .T₂₁A₂₂A₂₃A₂₄T₂₅G₂₆g₂₇g₂₈g₂₉g₃₀g₃₁g₃₂S₃₃-3′  (17)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (17) hasat least about 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence ofSEQ ID NO.: 17. Such oligonucleotide decoys can bind to ternary complexfactors. In certain embodiments, such oligonucleotide decoys can bind toone or more transcription factors closely related to ternary complexfactors, such as SRF.

In certain embodiments, an oligonucleotide decoy represented by formula(17) comprises a deletion of one or more (e.g., 1, 2, 3, 4 or 5)nucleotides selected from the group consisting of g₁₅, g₁₆, c₁₇, c₁₈ andt₁₉. In certain embodiments, oligonucleotide decoys comprising adeletion of one or more nucleotides selected from the group consistingof g₁₅, g₁₆, c₁₇, c₁₈ and t₁₉ have at least 70% identity to thenucleotide sequence of SEQ ID NO.: 17.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (18):

5′-S₁n₂n₃n₄n₅n₆n₇W₈W₉C₁₀G₁₁C₁₂G₁₃G₁₄w₁₅w₁₆g₁₇g₁₈w₁₉w₂₀ . . .w₂₁C₂₂C₂₃G₂₄G₂₅W₂₆W₂₇n₂₈n₂₉n₃₀n₃₁n₃₂S₃₃-3′  (18)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can an A or a T, lower caseletters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (18) has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO.:18. Such oligonucleotide decoys can bind to STAT1 transcription factor.In certain embodiments, such oligonucleotide decoys can bind to one ormore transcription factors closely related to STAT1 transcriptionfactor, such as STAT2-6.

In certain embodiments, an oligonucleotide decoy represented by formula(18) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6 or 7)nucleotides selected from the group consisting of w₁₅, w₁₆, g₁₇, g₁₈,w₁₉, w₂₀ and w₂₁. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of w₁₅, w₁₆, g₁₇, g₁₈, w₁₉, w₂₀ and w₂₁ have at least 90%identity to the nucleotide sequence of SEQ ID NO.: 18.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (19):

5′-S₁n₂n₃n₄T₅G₆C₇C₈T₉T₁₀A₁₁T₁₂C₁₃T₁₄c₁₅t₁₆n₁₇n₁₈g₁₉g₂₀ . . .G₂₁A₂₂T₂₃A₂₄A₂₅S₂₆n₂₇n₂₈n₂₉n₃₀S₃₁-3′  (19)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (19) hasat least about 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence ofSEQ ID NO.: 19. Such oligonucleotide decoys can bind to GATA1transcription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toGATA1 transcription factor, such as GATA2-4.

In certain embodiments, an oligonucleotide decoy represented by formula(19) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5 or 6)nucleotides selected from the group consisting of c₁₅, t₁₆, n₁₇, n₁₈,g₁₉ and g₂₀. In certain embodiments, oligonucleotide decoys comprising adeletion of one or more nucleotides selected from the group consistingof c₁₅, t₁₆, n₁₇, n₁₈, g₁₉ and g₂₀ have at least 65% identity to thenucleotide sequence of SEQ ID NO.: 19.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (20):

5′-S₁n₂n₃n₄n₅n₆T₇G₈A₉A₁₀T₁₁w₁₂w₁₃g₁₄a₁₅g₁₆g₁₇a₁₈a₁₉a₂₀ . . .a₂₁w₂₂w₂₃G₂₄C₂₅A₂₆T₂₇G₂₈C₂₉n₃₀n₃₁S₃₂-3′  (20)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can an A or a T, lower caseletters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (20) has at least about 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotidesequence of SEQ ID NO.: 20. Such oligonucleotide decoys can bind to ELF1transcription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toELF1 transcription factor, such as POU1F1.

In certain embodiments, an oligonucleotide decoy represented by formula(20) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12) nucleotides selected from the group consisting of w₁₂,w₁₃, g₁₄, a₁₅, g₁₆, g₁₇, a₁₈, a₁₉, a₂₀, a₂₁, w₂₂ and w₂₃. In certainembodiments, oligonucleotide decoys comprising a deletion of one or morenucleotides selected from the group consisting of w₁₂, w₁₃, g₁₄, a₁₅,g₁₆, g₁₇, a₁₈, a₁₉, a₂₀, a₂₁, w₂₂ and w₂₃ have a t least 65% identity tothe nucleotide sequence of SEQ ID NO.: 20

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (21):

5′-S₁n₂n₃n₄n₅G₆A₇G₈A₉T₁₀T₁₁k₁₂c₁₃a₁₄c₁₅n₁₆n₁₇n₁₈g₁₉a₂₀ . . .g₂₁a₂₂t₂₃T₂₄K₂₅C₂₆A₂₇C₂₈n₂₉n₃₀n₃₁n₃₂S₃₃-3′  (21)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “K” can be a G or a T, lowercase letters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (21) has at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to thenucleotide sequence of SEQ ID NO.: 21. Such oligonucleotide decoys canbind to “nuclear factor—granulocyte/macrophage a” transcription factors.In certain embodiments, such oligonucleotide decoys can bind to one ormore transcription factors closely related to “nuclearfactor—granulocyte/macrophage a” transcription factors, such as “nuclearfactor—granulocyte/macrophage b-c”.

In certain embodiments, an oligonucleotide decoy represented by formula(21) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12) nucleotides selected from the group consisting of k₁₂,c₁₃, a₁₄, c₁₅, n₁₆, n₁₇, n₁₈, g₁₉, a₂₀, g₂₁, a₂₂ and t₂₃. In certainembodiments, oligonucleotide decoys comprising a deletion of one or morenucleotides selected from the group consisting of k₁₂, c₁₃, a₁₄, c₁₅,n₁₆, n₁₇, n₁₈, g₁₉, a₂₀, g₂₁, a₂₂ and t₂₃ have at least 60% identity tothe nucleotide sequence of SEQ ID NO.: 21.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (22):

5′-S₁n₂n₃n₄n₅K₆C₇M₈T₉W₁₀A₁₁W₁₂t₁₃r₁₄m₁₅w₁₆n₁₇r₁₈m₁₉w₂₀ . . .K₂₁C₂₂M₂₃T₂₄W₂₅A₂₆W₂₇T₂₈n₂₉n₃₀n₃₁S₃₂-3′  (22)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can an A or a T, “K” can bea G or a T, “M” can be an A or a C, “R” can be an A or a G, lower caseletters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (22) has at least about 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotidesequence of SEQ ID NO.: 22. Such oligonucleotide decoys can bind toPOU4F1 transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to POU4F1 transcription factor, such as POU4F2-3.

In certain embodiments, an oligonucleotide decoy represented by formula(22) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or8) nucleotides selected from the group consisting of t₁₃, r₁₄, m₁₅, w₁₆,n₁₇, r₁₈, m₁₉ and w₂₀. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of t₁₃, r₁₄, m₁₅, w₁₆, n₁₇, r₁₈, m₁₉ and w₂₀ have at least65% identity to the nucleotide sequence of SEQ ID NO.: 22.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (23):

5′-S₁n₂n₃n₄A₅G₆K₇Y₈A₉A₁₀D₁₁N₁₂D₁₃T₁₄h₁₅h₁₆h₁₇n₁₈n₁₉n₂₀ . . .h₂₁h₂₂H₂₃Y₂₄A₂₅A₂₆D₂₇N₂₈D₂₉T₃₀W₃₁V₃₂M₃₃t₃₄g₃₅c₃₆-3′  (23)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “V” can beG, A or C, “K” can be T or G, “D” can be G, A or T, “H” can be A, T orC, “W” can be A or T, lower case letters can optionally be deleted, andthe numbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (23) has at least about 55%, 60%, 65%,70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity to the nucleotide sequence of SEQ ID NO.: 23. Sucholigonucleotide decoys can bind to HNF1A transcription factor. Incertain embodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to HNF1A transcription factor,such as HNF1B-C.

In certain embodiments, an oligonucleotide decoy represented by formula(23) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or8) nucleotides selected from the group consisting of h₁₅, h₁₆, h₁₇, n₁₈,n₁₉, n₂₀, h₂₁ and h₂₂. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of h₁₅, h₁₆, h₁₇, n₁₈, n₁₉, n₂₀, h₂₁ and h₂₂ have at least55% identity to the nucleotide sequence of SEQ ID NO.: 23.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (24):

5′-S₁n₂n₃n₄n₅A₆A₇T₈A₉A₁₀t₁₁n₁₂n₁₃a₁₄t₁₅T₁₆A₁₇T₁₈T₁₉w₂₀ . . .w₂₁n₂₂n₂₃n₂₄S₂₅-3′  (24)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, lowercase letters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (24) has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence ofSEQ ID NO.: 24. Such oligonucleotide decoys can bind to ZFHX3transcription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toZFHX3 transcription factor, such as ZFHX-2, -4.

In certain embodiments, an oligonucleotide decoy represented by formula(24) comprises a deletion of one or more (e.g., 1, 2, 3, 4 or 5)nucleotides selected from the group consisting of t₁₁, n₁₂, n₁₃, a₁₄ andt₁₅. In certain embodiments, oligonucleotide decoys comprising adeletion of one or more nucleotides selected from the group consistingof t₁₁, n₁₂, n₁₃, a₁₄ and t1shave at least 80% identity to thenucleotide sequence of SEQ ID NO.: 24.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (25):

5′-S₁n₂n₃n₄S₅D₆H₇W₈M₉S₁₀H₁₁k₁₂w₁₃w₁₄m₁₅c₁₆s₁₇s₁₈d₁₉h₂₀ . . .w₂₁m₂₂s₂₃h₂₄K₂₅W₂₆W₂₇M₂₈C₂₉S₃₀n₃₁n₃₂n₃₃n₃₄S₃₅-3′  (25)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or T, “D” canbe A, G or T, “H” can be A, C or T, “M” can be A or C, “K” can be G orT, lower case letters can optionally be deleted, and the numbers insubscript represent the position of a nucleotide in the sequence.Although the formula shows a single strand, it should be understood thata complementary strand is included as part of the structure. Inpreferred embodiments, an oligonucleotide decoy having a sequencerepresented by formula (25) has at least about 80%, 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotidesequence of SEQ ID NO.: 25. Such oligonucleotide decoys can bind to IRF1transcription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toIRF1 transcription factor, such as IRF2.

In certain embodiments, an oligonucleotide decoy represented by formula(25) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12 or 13) nucleotides selected from the group consisting ofk₁₂, w₁₃, w₁₄, m₁₅, c₁₆, s₁₇, s₁₈, d₁₉, h₂₀, w₂₁, m₂₂, s₂₃ and h₂₄. Incertain embodiments, oligonucleotide decoys comprising a deletion of oneor more nucleotides selected from the group consisting of k₁₂, w₁₃, w₁₄,m₁₅, c₁₆, s₁₇, s₁₈, d₁₉, h₂₀, w₂₁, m₂₂, s₂₃ and h₂₄ have at least 80%identity to the nucleotide sequence of SEQ ID NO.: 25.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (26):

5′-S₁n₂n₃n₄y₅k₆g₇y₈k₉G₁₀A₁₁A₁₂y₁₃h₁₄b₁₅b₁₆n₁₇n₁₈n₁₉y₂₀ . . .h₂₁b₂₂b₂₃k₂₄G₂₅A₂₆A₂₇T₂₈A₂₉T₃₀C₃₁n₃₂n₃₃S₃₄-3′  (26)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “V” can be G, A or C, “K” can be T or G, “D” can be G, A or T, “H” can be A, T or G,“B” can be C, G or T, lower case letters can optionally be deleted, andthe numbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (26) has at least about 60%, 65%, 70%,75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to the nucleotide sequence of SEQ ID NO.: 26. Sucholigonucleotide decoys can bind to TEAD1 transcription factor. Incertain embodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to TEAD1 transcription factor,such as TEAD2-4.

In certain embodiments, an oligonucleotide decoy represented by formula(26) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12) nucleotides selected from the group consisting of y₁₃,h₁₄, b₁₅, b₁₆, n₁₇, n₁₈, n₁₉, y₂₀, h₂₁, b₂₂, b₂₃ and k₂₄. In certainembodiments, oligonucleotide decoys comprising a deletion of one or morenucleotides selected from the group consisting of y₁₃, h₁₄, b₁₅, b₁₆,n₁₇, n₁₈, n₁₉, y₂₀, h₂₁, b₂₂, b₂₃ and k₂₄ have at least 60% identity tothe nucleotide sequence of SEQ ID NO.: 26.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (27):

5′-S₁n₂n₃n₄T₅A₆T₇A₈W₉w₁₀w₁₁n₁₂n₁₃d₁₄n₁₅t₁₆a₁₇t₁₈A₁₉W₂₀ . . .w₂₁w₂₂n₂₃n₂₄w₂₅W₂₆T₂₇A₂₈A₂₉D₃₀W₃₁n₃₂n₃₃n₃₄n₃₅n₃₆S₃₇-3′  (27)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, “D” canbe an A, G or a T, lower case letters can optionally be deleted, and thenumbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (27) has at least about 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity tothe nucleotide sequence of SEQ ID NO.: 27. Such oligonucleotide decoyscan bind to TBP transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to TBP transcription factor, such as TBPL1-2.

In certain embodiments, an oligonucleotide decoy represented by formula(27) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13 or 14) nucleotides selected from the group consistingof w₁₀, w₁₁, n₁₂, n₁₃, d₁₄, n₁₅, t₁₆, a₁₇, t₁₈, w₂₁, w₂₂, n₂₃, n₂₄, andw₂₅. In certain embodiments, oligonucleotide decoys comprising adeletion of one or more nucleotides selected from the group consistingof w₁₀, w₁₁, n₁₂, n₁₃, d₁₄, n₁₅, t₁₆, a₁₇, t₁₈, w₂₁, w₂₂, n₂₃, n₂₄, andw₂₅ have a t least 75% identity to the nucleotide sequence of SEQ IDNO.: 27.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (28):

5′-S₁n₂n₃n₄T₅A₆T₇A₈A₉W₁₀W₁₁n₁₂n₁₃n₁₄n₁₅w₁₆w₁₇w₁₈A₁₉A₂₀ . . .W₂₁W₂₂k₂₃n₂₄n₂₅n₂₆n₂₇n₂₈S₂₉-3′  (28)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, “K” canbe a G or a T, lower case letters can optionally be deleted, and thenumbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (28) has at least about 65%, 70%, 75%,80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity to the nucleotide sequence of SEQ ID NO.: 28. Sucholigonucleotide decoys can bind to TBP transcription factors. In certainembodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to TBP transcription factors, suchas TBPL1 -2.

In certain embodiments, an oligonucleotide decoy represented by formula(28) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6 or 7)nucleotides selected from the group consisting of n₁₂, n₁₃, n₁₄, n₁₅,w₁₆, w₁₇ and w₁₈. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of n₁₂, n₁₃, n₁₄, n₁₅, w₁₆, w₁₇ and w₁₈ have at least 65%identity to the nucleotide sequence of SEQ ID NO.: 28.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (29):

5′-N₁n₂n₃C₄T₅G₆M₇K₈Y₉K₁₀K₁₁Y₁₂t₁₃m₁₄b₁₅y₁₆C₁₇A₁₈A₁₉T₂₀ . . .s₂₁d₂₂n₂₃n₂₄n₂₅S₂₆-3′  (29)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “M” can be an A or a C, “K” canbe a G or a T, “Y” can be a C or a T, “B” can be a C, G or T, “D” can bean A, G or T, lower case letters can optionally be deleted, and thenumbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (29) has at least about 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity tothe nucleotide sequence of SEQ ID NO.: 29. Such oligonucleotide decoyscan bind to NFYA transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to NFYA transcription factor, such as NFYB-C.

In certain embodiments, an oligonucleotide decoy represented by formula(29) comprises a deletion of one or more (e.g., 1, 2, 3 or 4)nucleotides selected from the group consisting of t₁₃, m₁₄, b₁₅ and y₁₆.In certain embodiments, oligonucleotide decoys comprising a deletion ofone or more nucleotides selected from the group consisting of t₁₃, m₁₄,b₁₅ and y₁₆ have at least 75% identity to the nucleotide sequence of SEQID NO.: 29.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (30):

5′-S₁n₂n₃T₄C₅T₆C₇Y₈G₉A₁₀T₁₁T₁₂G₁₃G₁₄Y₁₅y₁₆h₁₇y₁₈b₁₉n₂₀ . . .n₂₁n₂₂y₂₃y₂₄h₂₅h₂₆v₂₇G₂₈A₂₉T₃₀T₃₁G₃₂G₃₃Y₃₄T₃₅C₃₆B₃₇Y₃₈n₃₉S₄₀-3′  (30)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “H” can beA, T or C, “B” can be C, G or T, lower case letters can optionally bedeleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (30) has at least about 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence ofSEQ ID NO.: 30. Such oligonucleotide decoys can bind to NFYAtranscription factor. In certain embodiments, such oligonucleotidedecoys can bind to one or more transcription factors closely related toNFYA transcription factor, such as NFYB-C.

In certain embodiments, an oligonucleotide decoy represented by formula(30) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12) nucleotides selected from the group consisting of y₁₆,h₁₇, y₁₈, b₁₉, n₂₀, n₂₁, n₂₂, y₂₃, y₂₄, h₂₅, h₂₆ and v₂₇. In certainembodiments, oligonucleotide decoys comprising a deletion of one or morenucleotides selected from the group consisting of y₁₆, h₁₇, y₁₈, b₁₉,n₂₀, n₂₁, n₂₂, y₂₃, y₂₄, h₂₅, h₂₆ and v₂₇ have at least 50% identity tothe nucleotide sequence of SEQ ID NO.: 30.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (31):

5′-S₁n₂n₃C₄A₅C₆C₇C₈s₉a₁₀s₁₁s₁₂s₁₃w₁₄s₁₅s₁₆s₁₇w₁₈C₁₉A₂₀ . . .C₂₁C₂₂C₂₃a₂₄n₂₅n₂₆n₂₇S28-3′  (31)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, lowercase letters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (31) has at least about 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotide sequenceof SEQ ID NO.: 31. Such oligonucleotide decoys can bind to CACCC-boxbinding factors.

In certain embodiments, an oligonucleotide decoy represented by formula(31) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9 or 10) nucleotides selected from the group consisting of s₉, a₁₀, s₁₁,s₁₂, s₁₃, w₁₄, s₁₅, s₁₆, s₁₇ and w₁₈. In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of s₉, a₁₀, s₁₁, s₁₂, s₁₃, w₁₄, s₁₅,s₁₆, s₁₇ and w₁₈ have at least 75% identity to the nucleotide sequenceof SEQ ID NO.: 31.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (32):

5′-S₁n₂n₃C₄C₅T₆W₇T₈G₉C₁₀C₁₁T₁₂y₁₃y₁₄y₁₅y₁₆y₁₇n₁₈n₁₉n₂₀ . . .y₂₁y₂₂y₂₃y₂₄y₂₅G₂₆C₂₇C₂₈T₂₉C₃₀C₃₁T₃₂W₃₃S₃₄n₃₅n₃₆S₃₇-3′  (32)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “W” can be Aor T, lower case letters can optionally be deleted, and the numbers insubscript represent the position of a nucleotide in the sequence.Although the formula shows a single strand, it should be understood thata complementary strand is included as part of the structure. Inpreferred embodiments, an oligonucleotide decoy having a sequencerepresented by formula (32) has at least about 50%, 55%, 60%, 65%70%,75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to the nucleotide sequence of SEQ ID NO.: 32. Sucholigonucleotide decoys can bind to KLF4 transcription factor. In certainembodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to KLF4 transcription factor, suchas KLF-1, -5.

In certain embodiments, an oligonucleotide decoy represented by formula(32) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12 or 13) nucleotides selected from the group consisting ofy₁₃, y₁₄, y₁₅, y₁₆, y₁₇, n₁₈, n₁₉, n₂₀, y₂₁, y₂₂, y₂₃, y₂₄ and y₂₅. Incertain embodiments, oligonucleotide decoys comprising a deletion of oneor more nucleotides selected from the group consisting of y₁₃, y₁₄, y₁₅,y₁₆, y₁₇, n₁₈, n₁₉, n₂₀, y₂₁, y₂₂, y₂₃, y₂₄ and y₂₅ have at least 50%identity to the nucleotide sequence of SEQ ID NO.: 32.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (33):

5′-S₁n₂n₃n₄W₅W₆W₇G₈G₉G₁₀w₁₁d₁₂g₁₃n₁₄n₁₅w₁₆w₁₇w₁₈G₁₉G₂₀ . . .G₂₁W₂₂D₂₃G₂₄n₂₅n₂₆n₂₇n₂₈S₂₉-3′  (33)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, “D” canbe an A, G or T, lower case letters can optionally be deleted, and thenumbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (33) has at least about 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity tothe nucleotide sequence of SEQ ID NO.: 33. Such oligonucleotide decoyscan bind to KLF7 transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to KLF7 transcription factor, such as KLF-1, -2, and -5.

In certain embodiments, an oligonucleotide decoy represented by formula(33) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or8) nucleotides selected from the group consisting of w₁₁, d₁₂, g₁₃, n₁₄,n₁₅, w₁₆, w₁₇ and w₁₈. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of w₁₁, d₁₂, g₁₃, n₁₄, n₁₅, w₁₆, w₁₇ and wis have at least75% identity to the nucleotide sequence of SEQ ID NO.: 33.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (34):

5′-S1w₂w₃w₄w₅w₆C₇A₈C₉T₁₀C₁₁A₁₂G₁₃C₁₄w₁₅w₁₆w₁₇w₁₈c₁₉g₂₀ . . .g₂₁w₂₂g₂₃w₂₄G₂₅G₂₆G₂₇W₂₈W₂₉g₃₀w₃₁w₃₂w₃₃w₃₄w₃₅S₃₆-3′  )34)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, lowercase letters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (34) has at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to thenucleotide sequence of SEQ ID NO.: 34. Such oligonucleotide decoys canbind to MAFG transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to MAFG transcription factor, such as MAF-A, -B, -F, -K.

In certain embodiments, an oligonucleotide decoy represented by formula(34) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9 or 10) nucleotides selected from the group consisting of w₁₅, w₁₆,w₁₇, w₁₈, c₁₉, g₂₀, g₂₁, w₂₂, g₂₃ and w₂₄. In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of w₁₅, w₁₆, w₁₇, w₁₈, c₁₉, g₂₀, g₂₁,w₂₂, g₂₃ and w₂₄ have at least 55% identity to the nucleotide sequenceof SEQ ID NO.: 34.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (35):

5′-S₁n₂n₃w₄B₅Y₆A₇G₈Y₉A₁₀C₁₁C1₂D₁₃N₁₄R₁₅G₁₆H₁₇S₁₈A₁₉G₂₀ . . .C₂₁N₂₂N₂₃N₂₄n₂₅n₂₆n₂₇W₂₈B₂₉Y₃₀A₃₁G₃₂Y₃₃A₃₄C₃₅C₃₆D₃₇N₃₈R₃₉G₄₀ . . .H₄₁S₄₂A₄₃G₄₄C₄₅N₄₆N₄₇H₄₈n₄₉n₅₀S₅₁-3′  (35)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, Y canbe a C or a T, “H” can be an A, T or a C, “R” can be G or A, “D” can beG, A or T, “Y” can be C or T, “B” can be C,G or T, lower case letterscan optionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (35) hasat least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to thenucleotide sequence of SEQ ID NO.: 35. Such oligonucleotide decoys canbind to REST transcription factor.

In certain embodiments, an oligonucleotide decoy represented by formula(35) comprises a deletion of one or more (e.g., 1, 2 or 3) nucleotidesselected from the group consisting of n₂₅, n₂₆ and n₂₇. In certainembodiments, oligonucleotide decoys comprising a deletion of one or morenucleotides selected from the group consisting of n₂₅, n₂₆ and n₂₇ haveat least 50% identity to the nucleotide sequence of SEQ ID NO.: 35.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (36):

5′-S₁n₂n₃n₄n₅G₆A₇R₈M₉A₁₀W₁₁k₁₂s₁₃a₁₄g₁₅k₁₆n₁₇n₁₈n₁₉n₂₀ . . .g₂₁a₂₂r₂₃m₂₄A₂₅W₂₆K₂₇S₂₈A₂₉G₃₀K₃₁n₃₂n₃₃n₃₄n₃₅S₃₆₋3′  (36)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, “M” canbe A or C, “R” can be A or G, “K” can be G or T, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (36) hasat least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotide sequenceof SEQ ID NO.: 36. Such oligonucleotide decoys can bind to KCNIP3transcription factor.

In certain embodiments, an oligonucleotide decoy represented by formula(36) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12 or 13) nucleotides selected from the group consisting ofk₁₂, s₁₃, a₁₄, g₁₅, k₁₆, n₁₇, n₁₈, n₁₉, n₂₀, g₂₁, a₂₂, r₂₃ and m₂₄. Incertain embodiments, oligonucleotide decoys comprising a deletion of oneor more nucleotides selected from the group consisting of k₁₂, s₁₃, a₁₄,g₁₅, k₁₆, n₁₇, n₁₈, n₁₉, n₂₀, g₂₁, a₂₂, r₂₃ and m₂₄ have at least 60%identity to the nucleotide sequence of SEQ ID NO.: 36.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (37):

5′-S₁n₂n₃n₄n₅G₆A₇R₈G₉C₁₀C₁₁S₁₂s₁₃w₁₄g₁₅w₁₆n₁₇n₁₈n₁₉n₂₀ . . .g₂₁a₂₂r₂₃G₂₄C₂₅C₂₆S₂₇S₂₈W₂₉G₃₀W₃₁n₃₂n₃₃n₃₄S₃₅-3′  (37)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, “M” canbe A or C, “R” can be A or G, lower case letters can optionally bedeleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (37) has at least about 75%,80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity to the nucleotide sequence of SEQ ID NO.: 37. Sucholigonucleotide decoys can bind to KCNIP3 transcription factor.

In certain embodiments, an oligonucleotide decoy represented by formula(37) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10 or 11) nucleotides selected from the group consisting of s₁₃, w₁₄,g₁₅, w₁₆, n₁₇, n₁₈, n₁₉, n₂₀, g₂₁, a₂₂ and r₂₃. In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of s₁₃, w₁₄, g₁₅, w₁₆, n₁₇, n₁₈, n₁,n₂₀, g₂₁, a₂₂ and r₂₃ have at least 75% identity to the nucleotidesequence of SEQ ID NO.: 37.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (38):

5′-s₁C₂G₃A₄A₅A₆G₇G₈A₉C₁₀A₁₁A₁₂A₁₃s₁₄s₁₅n₁₆v₁₇v₁₈n₁₉n₂₀ . . .n₂₁s₂₂g₂₃d₂₄n₂₅n₂₆G₂₇G₂₈A₂₉C₃₀A₃₁A₃₂A₃₃G₃₄G₃₅T₃₆C₃₇A₃₈s₃₉-3′  (38)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “V” can be A, C or G, “D” canbe G, A or T, lower case letters can optionally be deleted, and thenumbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (38) has at least about 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO.:38. Such oligonucleotide decoys can bind to PPARA transcription factor.In certain embodiments, such oligonucleotide decoys can bind to one ormore transcription factors closely related to PPARA transcriptionfactor, such as PPAR-D, -G.

In certain embodiments, an oligonucleotide decoy represented by formula(38) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9 or 10) nucleotides selected from the group consisting of s₁₄, s₁₅,n₁₆, v₁₇, v₁₈, n₁₉, n₂₀, n₂₁, s₂₂ and g₂₃. In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of s₁₄, s₁₅, n₁₆, v₁₇, v₁₈, n₁₉, n₂₀,n₂₁, s₂₂ and g₂₃ have at least 50% identity to the nucleotide sequenceof SEQ ID NO.: 38.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (39):

5′-S₁n₂n₃n₄A₅R₆M₇R₈W₉W₁₀y₁₁w₁₂m₁₃g₁₄n₁₅n₁₆a₁₇r₁₈m₁₉r₂₀ . . .w₂₁w₂₂y₂₃W₂₄M₂₅G₂₆A₂₇A₂₈T₂₉T₃₀n₃₁n₃₂n₃₃n₃₄S₃₅-3′  (39)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, “R” canbe A or G, “M” can be an A or a C, “Y” can be a C or a T, lower caseletters can optionally be deleted, and the numbers in subscriptrepresent the position of a nucleotide in the sequence. Although theformula shows a single strand, it should be understood that acomplementary strand is included as part of the structure. In preferredembodiments, an oligonucleotide decoy having a sequence represented byformula (39) has at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to thenucleotide sequence of SEQ ID NO.: 39. Such oligonucleotide decoys canbind to HSF1 transcription factor. In certain embodiments, theoligonucleotide decoys can bind to one or more transcription factorsclosely related to HSF1 transcription factor, such as HSF2.

In certain embodiments, an oligonucleotide decoy represented by formula(39) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12 or 13) nucleotides selected from the group consisting ofy₁₁, w₁₂, M₁₃, g₁₄, n₁₅, n₁₆, a₁₇, r₁₈, m₁₉, r₂₀, w₂₁, w₂₂ and y₂₃. Incertain embodiments, oligonucleotide decoys comprising a deletion of oneor more nucleotides selected from the group consisting of y₁₁, w_(1,2)m₁₃, g₁₄, n₁₅, n₁₆, a₁₇, r₁₈, m₁₉, r₂₀, w₂₁, w₂₂ and y₂₃ have at least55% identity to the nucleotide sequence of SEQ ID NO.: 39.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (47):

5′-S₁n₂n₃n₄n₅n₆C₇A₈C₉T₁₀T₁₁C₁₂C₁₃T₁₄G₁₅C₁₆n₁₇n₁₈n₁₉n₂₀n₂₁S₂₂- 3′  (47)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, lower case letters canoptionally be deleted, and the numbers in subscript represent theposition of a nucleotide in the sequence. Although the formula shows asingle strand, it should be understood that a complementary strand isincluded as part of the structure. In preferred embodiments, anoligonucleotide decoy having a sequence represented by formula (47) hasat least about 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO.:47. Such oligonucleotide decoys can bind to ELK1 transcription factor.In certain embodiments, such oligonucleotide decoys can bind to one ormore transcription factors closely related to ELK1 transcription factor,such as ETS1.

In certain embodiments, an oligonucleotide decoy represented by formula(47) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9 or 10) nucleotides selected from the group consisting of n₂, n₃, n₄,n₅, n₆, n₁₇, n₁₈, n₁₉, n₂₀ and n₂₁. In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of n₂, n₃, n₄, n₅, n₆, n₁₇, n₁₈, n₁₉,n₂₀ and n₂₁ have at least 80% identity to the nucleotide sequence of SEQID NO.: 47.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (48):

5′-S₁n₂n₃n₄n₅n₆A7G₈K₉Y₁₀A₁₁A₁₂D₁₃N₁₄D₁₅T₁₆W₁₇V₁₈M₁₉N₂₀ . . .n₂₁n₂₂n₂₃n₂₄n₂₅S₂₆-3′  (48)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “V” can beG, A or C, “K” can be T or G, “D” can be G, A or T, “W” can be A or T,“M” can be C or A, lower case letters can optionally be deleted, and thenumbers in subscript represent the position of a nucleotide in thesequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (48) has at least about 70%, 75%, 80%,85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity to the nucleotide sequence of SEQ ID NO.: 48. Sucholigonucleotide decoys can bind to HNF1A transcription factor. Incertain embodiments, such oligonucleotide decoys can bind to one or moretranscription factors closely related to HNF1A transcription factor,such as HNF1B-C.

In certain embodiments, an oligonucleotide decoy represented by formula(48) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9 or 10) nucleotides selected from the group consisting of n₂, n₃, n₄,n₅, n₆, n₂₁, n₂₂, n₂₃, n₂₄ and n_(25.) In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of n₂, n₃, n₄, n₅, n₆, n₂₁, n₂₂, n₂₃,n₂₄ and n₂₅ have at least 70% identity to the nucleotide sequence of SEQID NO.: 48.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (49):

5′-S₁n₂n₃T₄C₅T₆C₇Y₈G₉A₁₀T₁₁T₁₂G₁₃G₁₄Y₁₅T₁₆C₁₇B₁₈Y₁₉n₂₀S₂₁-3′   (49)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “B” can beC, G or T, lower case letters can optionally be deleted, and the numbersin subscript represent the position of a nucleotide in the sequence.Although the formula shows a single strand, it should be understood thata complementary strand is included as part of the structure. Inpreferred embodiments, an oligonucleotide decoy having a sequencerepresented by formula (49) has at least about 80%, 85%, 88%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to thenucleotide sequence of SEQ ID NO.: 49. Such oligonucleotide decoys canbind to NFYA transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to NFYA transcription factor, such as NFYB-C.

In certain embodiments, an oligonucleotide decoy represented by formula(49) comprises a deletion of one or more (e.g., 1, 2 or 3) nucleotidesselected from the group consisting of n₂, n₃ and n₂₀. In certainembodiments, oligonucleotide decoys comprising a deletion of one or morenucleotides selected from the group consisting of n₂, n₃ and n₂₀have atleast 80% identity to the nucleotide sequence of SEQ ID NO.: 49.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (50):

5′-S₁n₂n₃n₄n₅n₆C₇C₈T₉W₁₀T₁₁G₁₂C₁₃C₁₄T₁₅C₁₆C₁₇T₁₈W₁₉S₂₀ . . .r₂₁r₂₂n₂₃n₂₄n₂₅S₂₆-3′  (50)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be A or T, “R” can be Gor A, lower case letters can optionally be deleted, and the numbers insubscript represent the position of a nucleotide in the sequence.Although the formula shows a single strand, it should be understood thata complementary strand is included as part of the structure. Inpreferred embodiments, an oligonucleotide decoy having a sequencerepresented by formula (50) has at least about 75%, 80%, 85%, 88%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to thenucleotide sequence of SEQ ID NO.: 50. Such oligonucleotide decoys canbind to KLF4 transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to KLF4 transcription factor, such as KLF-1, -5.

In certain embodiments, an oligonucleotide decoy represented by formula(50) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9 or 10) nucleotides selected from the group consisting of n₂, n₃, n₄,n₅, n₆, r₂₁, r₂₂, n₂₃, n₂₄ and n_(25.) In certain embodiments,oligonucleotide decoys comprising a deletion of one or more nucleotidesselected from the group consisting of n₂, n₃, n₄, n₅, n₆, r₂₁, r₂₂, n₂₃,n₂₄ and n₂₅ have at least 75% identity to the nucleotide sequence of SEQID NO.: 50.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (51):

5′-S₁n₂n₃n₄n₅w₆B₇Y₈A₉G₁₀Y₁₁A₁₂C₁₃C₁₄D₁₅N₁₆R₁₇G₁₈H₁₉S₂₀ . . .A₂₁G₂₂C₂₃N₂₄N₂₅H₂₆n₂₇n₂₈n₂₉n₃₀S₃₁-3′  (51)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be an A or a T, “H” canbe an A, T or a C, “R” can be G or A, “D” can be G, A or T, “Y” can be Cor T, “B” can be C, G or T, lower case letters can optionally bedeleted, and the numbers in subscript represent the position of anucleotide in the sequence. Although the formula shows a single strand,it should be understood that a complementary strand is included as partof the structure. In preferred embodiments, an oligonucleotide decoyhaving a sequence represented by formula (51) has at least about 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to the nucleotide sequence of SEQ ID NO.: 51. Sucholigonucleotide decoys can bind to REST transcription factor.

In certain embodiments, an oligonucleotide decoy represented by formula(51) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or8) nucleotides selected from the group consisting of n₂, n₃, n₄, n₅,n₂₇, n₂₈, n₂₉ and n₃₀. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of n₂, n₃, n₄, n₅, n₂₇, n₂₈, n₂₉ and n₃₀ have at least 75%identity to the nucleotide sequence of SEQ ID NO.: 51.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (52):

5′-S₁m₂r₃m₄W₅A₆G₇G₈N₉C₁₀A₁₁A₁₂A₁₃G₁₄G₁₅T₁₆C₁₇A₁₈n₁₉n₂₀ . . .n₂₁n₂₂S₂₃-3′  (52)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “W” can be A or T, “R” can be Gor A, “M” can be C or A, lower case letters can optionally be deleted,and the numbers in subscript represent the position of a nucleotide inthe sequence. Although the formula shows a single strand, it should beunderstood that a complementary strand is included as part of thestructure. In preferred embodiments, an oligonucleotide decoy having asequence represented by formula (52) has at least about 80%, 85%, 88%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity tothe nucleotide sequence of SEQ ID NO.: 52. Such oligonucleotide decoyscan bind to PPARA transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to PPARA transcription factor, such as PPAR-D, -G.

In certain embodiments, an oligonucleotide decoy represented by formula(52) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or8) nucleotides selected from the group consisting of m₂, r₃, m₄, n₁₉,n₂₀, n₂₁, n₂₂ and g₂₃. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of m₂, r₃, m₄, n₁₉, n₂₀, n₂₁, n₂₂ and g_(23h) have at least80% identity to the nucleotide sequence of SEQ ID NO.: 52.

In certain embodiments, an oligonucleotide decoy comprises adouble-stranded sequence represented by formula (53):

5′-S₁s₂c₃t₄t₅g₆y₇k₈g₉y₁₀k₁₁G₁₂A₁₃A₁₄T₁₅A₁₆T₁₇c₁₈g₁₉n₂₀ . . .n₂₁n₂₂n₂₃n₂₄S₂₅-3′  (53)

wherein “A” is an adenine nucleotide, “C” is a cytosine nucleotide, “G”is a guanine nucleotide, “T” is a thymine nucleotide, “S” can be a G orC nucleotide, “N” can be any nucleotide, “Y” can be T or C, “K” can be Tor G, lower case letters can optionally be deleted, and the numbers insubscript represent the position of a nucleotide in the sequence.Although the formula shows a single strand, it should be understood thata complementary strand is included as part of the structure. Inpreferred embodiments, an oligonucleotide decoy having a sequencerepresented by formula (53) has at least about 75%, 80%, 85%, 88%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to thenucleotide sequence of SEQ ID NO.: 53. Such oligonucleotide decoys canbind to TEAD1 transcription factor. In certain embodiments, sucholigonucleotide decoys can bind to one or more transcription factorsclosely related to TEAD1 transcription factor, such as TEAD2-4.

In certain embodiments, an oligonucleotide decoy represented by formula(53) comprises a deletion of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16 or 17) nucleotides selected from the groupconsisting of s₂, c₃, t₄, t₅, g₆, y₇, k₈, g₉, y₁₀, k₁₁, c₁₈, g₁₉, n₂₀,n₂₁, n₂₂, n₂₃ and n₂₄. In certain embodiments, oligonucleotide decoyscomprising a deletion of one or more nucleotides selected from the groupconsisting of s₂, c₃, t₄, t₅, g₆, y₇, k₈, g₉, y₁₀, k₁₁, c₁₈, g₁₉, n₂₀,n₂₁, n₂₂, n₂₃ and n₂₄ have at least 75% identity to the nucleotidesequence of SEQ ID NO.: 53.

A double stranded oligonucleotide having a certain percent (e.g., 65%,70%, 75%, 80%, 85%, 90%, 95%, or 99%) of sequence identity with anothersequence means that, when aligned, that percentage determines the levelof correspondence of bases arrangement in comparing the two sequences.This alignment and the percent homology or identity can be determinedusing any suitable software program known in the art that allows localalignment. The software program should be capable of finding regions oflocal identity between two sequences without the need to include theentire length of the sequences. In some embodiments, such programincludes but is not limited to the EMBOSS Pairwise Alignment Algorithm(available from the European Bioinformatics Institute (EBI)), theClustalW program (also available from the European BioinformaticsInstitute (EBI)), or the BLAST program (BLAST Manual, Altschul et al.,Natl Cent. Biotechnol. Inf., Natl Lib. Med. (NCIB NLM NIH), Bethesda,Md., and Altschul et al., (1997) NAR 25:3389 3402).

One skilled in the art will recognize that sequences encompassed hereininclude those that hybridize under stringent hybridization conditionswith an exemplified sequence (e.g., SEQ ID NOs.: 1-42, 45, and 47-53). Anucleic acid is hybridizable to another nucleic acid when a singlestranded form of the nucleic acid can anneal to the other singlestranded nucleic acid under appropriate conditions of temperature andsolution ionic strength. Hybridization conditions are well known in theart. In some embodiments, annealing can occur during a slow decrease oftemperature from a denaturizing temperature (e.g., 100° C.) to roomtemperature in a salt containing solvent (e.g., Tris-EDTA buffer).

The oligonucleotide decoys disclosed herein can be chemically modifiedby methods well known to the skilled artisan (e.g., incorporation ofphosphorothioate, methylphosphonate, phosphorodithioate,phosphoramidates, carbonate, thioether, siloxane, acetamidate orcarboxymethyl ester linkages between nucleotides) to prevent degradationby nucleases within cells and extra-cellular fluids (e.g., serum,cerebrospinal fluid). Also, oligonucleotide decoys can be designed thatform hairpin and dumbbell structures which also prevent or hindernuclease degradation. Further, the oligonucleotide decoys can also beinserted as a portion of a larger plasmid capable of episomalmaintenance or constitutive replication in the target cell in order toprovide longer term, enhanced intracellular exposure to the decoysequence or reduce its degradation. Accordingly, any chemicalmodification or structural alteration known in the art to enhanceoligonucleotide stability is within the scope of the present disclosure.In some embodiments, the oligonucleotide decoys disclosed herein can beattached, for example, to polyethylene glycol polymers, peptides (e.g.,a protein translocation domain) or proteins which improve thetherapeutic effect of oligonucleotide decoys. Such modifiedoligonucleotide decoys can preferentially traverse the cell membrane.

In certain embodiments, the oligonucleotide decoys are provided assalts, hydrates, solvates, or N-oxide derivatives. In certainembodiments, the oligonucleotide decoys are provided in solution (e.g.,a saline solution having a physiologic pH) or in lyophilized form. Inother embodiments, the oligonucleotide decoys are provided in liposomes.

In certain embodiments, oligonucleotide decoys include, but are notlimited to, sequences presented in Table A. In general, theoligonucleotide decoy is generated by annealing the sequence provided inthe table with a complementary sequence. To generate a mismatchdouble-stranded oligonucleotide, the sequence provided in the table canbe annealed to a sequence that is only partially complementary. Forexample, SEQ ID NO.: 43 can be annealed to SEQ ID NO.: 46 to produce themismatched sequence, SEQ ID NO.: 43/46.

TABLE A Oligonucleotide Sequences (5′-3′) SEQ ID NO.GGCTTATGCAAATTCGAATGCAAATTTGTCG SEQ ID NO.: 1CTAAGCCCACGTGACCATTGGCCAGGTGACCAGATC SEQ ID NO.: 2GTTATGCGTGGGCGATAATGCGGGGGCGTTATAG SEQ ID NO.: 3GCCTCCCTGAGCTCATTGACGTATCTCGG SEQ ID NO.: 4CGAATATGACTGAGAATGACTCAGATTTGC SEQ ID NO.: 5GGTTCTATGATTTTGGAATCGGATTGTGCAAAGAA SEQ ID NO.: 6 GCGCTTCAGGATGTCCATATTAGGAGATCTTGTTCG SEQ ID NO.: 7GGCCACAGGATGTAGGATGTCCATATTAGGATGC SEQ ID NO.: 8GTTCTCTAAAAATAAAAGGCTAAAAATAAAAGTCG SEQ ID NO.: 9 ATTAGGGGCGGGGTCCGGGGCGGGGTATTA SEQ ID NO.: 10GTTATGGCGGGGCGGGGCGGGGCCGGGCGGTTTAC SEQ ID NO.: 11GGCAATGTGGTTTTAGTGTGGTTTTACGG SEQ ID NO.: 12GCCGTTTGGGGTCATAGAACCACAGGAACCACACGG SEQ ID NO.: 13CATTGCCCGGAAATGGACCGGATGTAATTTCC SEQ ID NO.: 14GTTCTTGGAAAATAAATGGAAAATAGTGGAAAATAA SEQ ID NO.: 15 GTCGCGTTCCCACTTCCTGCGACCACTTCCTGCCGGG SEQ ID NO.: 16CTGCACCTATAAATGGCCTATAAATGGGGATGC SEQ ID NO.: 17GCTTATTTCGCGGAAGGTTTCCCGGAAGTGGCG SEQ ID NO.: 18GCTGTGCCTTATCTCTTTGGGATAACTGGCG SEQ ID NO.: 19GCTTAATGAATAAGAGGAAAAATGCATGCTGG SEQ ID NO.: 20GTTCTGAGATTGCACGATGAGATTTCACAGTCG SEQ ID NO.: 21GTCCCGCATAAATAATGGCATCCTTAATCGCG SEQ ID NO.: 22GTGCAGGCAAGAGTAGAGACAGGCAAGAGTAGATGC SEQ ID NO.: 23CCGCCAATAATTAATTATTAAGGCC SEQ ID NO.: 24GCTTCGTTCCATTTCCGGTCTCGGTTTCCCCATTC SEQ ID NO.: 25GCTGCTGTGGAATATCGACCTGTGGAATATCGTG SEQ ID NO.: 26GCCGTATAAATGTGCTATAAAAGTTTTAAGACCGT SEQ ID NO.: 27 GCGCCGTATAAATGTGCTATAAAAGCCGTGC SEQ ID NO.: 28 ATGCTGCGCTTTTCTCCAATCTGCGGSEQ ID NO.: 29 CGTTCTCCGATTGGTCACGGACTCTCCGATTGGTCA SEQ ID NO.: 30 CGGCGCGCACCCCAGCCTGGCTCACCCACGCG SEQ ID NO.: 31GATCCTTTGCCTCCTTCGATCCTTTGCCTCCTTCA SEQ ID NO.: 32 AGGGTGTTTGGGAGAGCTTTGGGAGGATACG SEQ ID NO.: 33GCTAATCACTCAGCATTTCGGTGAGGGAAGTGAAAG SEQ ID NO.: 34CCTTTCAGCACCACGGACAGCGCCAGCTTCAGCACC SEQ ID NO.: 35 ACGGACAGCGCCTCGGGATCGAACATGGAGTCAGTGAGAAATCAGGATCGG SEQ ID NO.: 36GGATCGAAGCCGGAGTCAAGGAGGCCCCTGATCGG SEQ ID NO.: 37CCGAAAGGACAAAGGTCAAGTCGAAAGGACAAAGGT SEQ ID NO.: 38 CAGCGGGAGAAAATTCGGGAACGTTCAAGAATTGTCGG SEQ ID NO.: 39GTTATGCGTGGGCGTAGATGCGGGGGCGTTATAG SEQ ID NO.: 40 GATGCGTGGGCGTAGGSEQ ID NO.: 41 GTATGCGTGGGCGGTGGGCGTAG SEQ ID NO.: 42GTTATGCGTTTGTAGATGCTTTCGTTATAG SEQ ID NO.: 43 GTTATGCGTGGGCGATATAGSEQ ID NO.: 44 GATGCGTGGGCGTTGACGTGGAAAATGC SEQ ID NO.: 45CTATTTCGAAACGATCTACATTGGCATAAC SEQ ID NO.: 46 CGTTCCCACTTCCTGCGACCGGSEQ ID NO.: 47 GGGTGAAGGCAAGAGTAGAGCGGCGG SEQ ID NO.: 48CGTTCTCCGATTGGTCACGCG SEQ ID NO.: 49 GTACTCCCTTTGCCTCCTTCAACCGGSEQ ID NO.: 50 CCTTATTCAGCACCACGGACAGCGCCATTCG SEQ ID NO.: 51GCGAAAGGACAAAGGTCAGGCGG SEQ ID NO.: 52 GGCTTGCTGTGGAATATCGATGGTGSEQ ID NO.: 53

According to the present invention, the composition of the presentinvention can further comprise a buffer. Any suitable buffer can be usedfor the composition of the present invention. In some embodiments, thebuffer system used for the composition is compatible with the activeingredient and/or the agent in the composition. In some otherembodiment, the buffer system used for the composition of the presentinvention facilitates or stabilizes the active ingredient and/or theagent. In some other embodiments, the buffer system used for thecomposition of the present invention is an organic or inorganic buffer.Examples of buffers include phosphate buffers, citrate buffers, boratebuffers, bicarbonate buffers, carbonate buffers, acetate buffers,ammonium buffers, and tromethamine (Tris) buffers.

According to the present invention, in some embodiments, when the activeingredient is an oligonucleotide and the agent is an ion, e.g., calcium,the buffer is a non-phosphate based buffer. The amount of bufferemployed will be ascertainable to a skilled artisan, such as an amountranging from 0.01 mM to 1 M, such as 10 mM.

According to the present invention, the composition of the presentinvention can be a pharmaceutical composition, e.g., including apharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers can contain a physiologically acceptable compound that acts,e.g., to stabilize the composition or to increase or decrease theabsorption of the active ingredient and/or pharmaceutical composition.Physiologically acceptable compounds can include, for example,carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, suchas ascorbic acid or glutathione, chelating agents, low molecular weightproteins, compositions that reduce the clearance or hydrolysis of anyco-administered agents, or excipient, or other stabilizers and/orbuffers. Detergents can also be used to stabilize the composition or toincrease or decrease absorption. One skilled in the art will appreciatethat the choice of a pharmaceutically acceptable carrier, including aphysiologically acceptable compound depends, e.g., on the route ofadministration of the present powders and on the particularphysio-chemical characteristics of any co-administered agent.

In some embodiments, suitable pharmaceutical carriers or vehiclesinclude excipients such as starch, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. In some embodiments, thepharmaceutical composition can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents can be used.

Pharmaceutical compositions can be manufactured by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions can be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds disclosed hereininto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsions, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, aerosols, sprays, suspensions, or any other form suitablefor use. Other examples of suitable pharmaceutical vehicles have beendescribed in the art (see Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 19th Edition, 1995).

According to another aspect of the invention, it provides methods forusing the composition of the present invention. In one embodiment, thecomposition of the present invention can be used to inhibit, reduce, orminimize one or more adverse effects of the active ingredient, e.g.,without the agent. In another embodiment, the composition of the presentinvention can be used to treat one or more conditions or diseasestreatable by the active ingredient, e.g., by administering thecomposition of the active ingredient and the agent, etc. In yet anotherembodiment, the composition of the present invention can be used totreat one or more conditions or diseases treatable by the activeingredient with decreased or reduced adverse effect(s) of the activeingredient. In still some embodiments, the active ingredient is anoligonucleotide decoy including one or more binding sites for EGR1 andthe composition of the present invention comprising the activeingredient can be used to treat pain or related conditions,

In general, “treating” or “treatment” of any condition, disease ordisorder refers, in some embodiments, to ameliorating the condition,disease or disorder (i.e., arresting or reducing the development of thedisease or at least one of the clinical symptoms thereof). In someembodiments “treating” or “treatment” refers to ameliorating at leastone physical parameter, which may not be discernible by the subject. Insome embodiments, “treating” or “treatment” refers to inhibiting thecondition, disease or disorder, either physically, (e.g., stabilizationof a discernible symptom), physiologically, (e.g., stabilization of aphysical parameter) or both. In some embodiments, “treating” or“treatment” refers to delaying the onset of a condition, disease, ordisorder.

The terms “minimizing,” “inhibiting,” and “reducing,” or any variationof these terms, includes any measurable decrease or complete inhibitionor reduction to achieve a desired result. For example, there may be adecrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivabletherein, reduction of activity compared to normal. “Prevention” or“preventing” refers to (1) a reduction in the risk of acquiring adisease or disorder (e.g., causing at least one of the clinical symptomsof a disease not to develop in a patient that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease), or (2) a reduction in the likely severity of asymptom associated with a disease or disorder (e.g., reducing the likelyseverity of at least one of the clinical symptoms of a disease in apatient that may be exposed to or predisposed to the disease but doesnot yet experience or display symptoms of the disease).

In still some embodiments, the active ingredient is an oligonucleotidedecoy including one or more binding sites for EGR1 and the compositionof the present invention comprising the active ingredient can be used totreat, pre-treat, or prevent pain or related conditions. In general,“pain” refers to an unpleasant sensory and emotional experience that isassociated with actual or potential tissue damage or described in suchterms. All of the different manifestations and qualities of pain,including mechanical pain (e.g., induced by a mechanical stimulus or bybody motion; mechanical hyperalgesia or allodynia), temperature-inducedpain (e.g., pain induced by hot, warm or cold temperatures), andchemically-induced pain (e.g., pain induced by a chemical) are included.In certain embodiments, pain is chronic, sub-chronic, acute, orsub-acute. “Chronic” refers to a period of time comprising months (e.g.,at least two months) or years. “Sub-acute” refers to a period of timecomprising hours (e.g., 1 h-24 h). “Sub-chronic” refers to a period oftime comprising days or months (e.g., less than two months). In certainembodiments, pain features hyperalgesia (i.e., an increased sensitivityto a painful stimulus) or allodynia (i.e., a painful response to ausually non-painful stimulus). Pain can be inflammatory pain,neuropathic pain, muscular pain, skeletal pain, post-surgery pain,arthritis pain, or diabetes pain. In certain embodiments, pain ispre-existing in a patient. In other embodiments, pain is iatrogenic,induced in a patient (e.g., post-operative pain).

In some embodiments, pain or pain related conditions include nociceptivesignaling. In general “nociceptive signaling” refers to molecular andcellular mechanisms involved in the detection of a noxious stimulus orof a potentially harmful stimulus, which leads to the perception ofpain, including neurotransmitter synthesis and release,neurotransmitter-induced signaling, membrane depolarization, and relatedintra-cellular and inter-cellular signaling events.

In some other embodiments, pain or pain related conditions includepost-operative pain, chronic pain, inflammatory pain, neuropathic pain,muscular pain, and skeletal pain. In certain embodiments, compositionscan be used for the prevention of one facet of pain while concurrentlytreating another symptom of pain.

In certain embodiments, the composition of the present invention can beused for treating or preventing pain in a patient by administering thecomposition of an oligonucleotide decoy and an agent, wherein theoligonucleotide decoy does not bind to the transcription factors AP1,ETS1 and STAT. In other embodiments, the composition of the presentinvention can be used for treating or preventing pain in a patient byadministering the composition of an oligonucleotide decoy and an agent,wherein the oligonucleotide decoy binds to one or more transcriptionfactors selected from the group consisting of AP1, ETS1, GATA and STATtranscription factors, provided that the pain is not lower back pain dueto an intervertebral disc disorder.

In certain embodiments, the composition of the present invention can beused for modulating transcription of a gene present in a cell involvedin nociceptive signaling or the perception of pain in a patient byadministering the composition of an oligonucleotide decoy, e.g., anoligonucleotide decoy comprising one or more EGR1 binding sites and anagent. In certain embodiments, modulation comprises suppressing orrepressing gene expression. “Modulation of gene expression level” refersto any change in gene expression level, including an induction oractivation (e.g., an increase in gene expression), an inhibition orsuppression (e.g., a decrease in gene expression), or a stabilization(e.g., prevention of the up-regulation or down-regulation of a gene thatordinarily occurs in response to a stimulus, such as a pain-inducingstimulus). In other embodiments, modulation comprises stabilizing geneexpression. In still other embodiments, modulation comprises activatingor inducing gene expression. In certain embodiments, the gene isinvolved in nociceptive signaling. Genes involved in nociceptivesignaling include, but are not limited to, genes encoding membraneproteins (e.g., ion channels, membrane receptors, etc.), solublesignaling molecules (e.g., intracellular signaling molecules orneurotransmitters), synthetic enzymes (e.g., neurotransmitter synthesisenzymes), and transcription factors. Specific examples of such genesinclude, but are not limited to, BDKRB2, HTR3A, SCN9A, BDNF, GRA15,NOS1, GCH1, CDK5R1, CACNA1B, P2XR3 and PNMT.

In other embodiments, the composition of the present invention can beused for modulating nociceptive signaling in a cell by contacting thecell with the composition of an oligonucleotide decoy, e.g., anoligonucleotide decoy comprising one or more EGR1 binding sites and anagent. In certain embodiments, modulation comprises suppressing orrepressing nociceptive signaling. In certain embodiments, modulatingnociceptive signaling in a cell comprises modulating, e.g., increasing,proteolysis of a protein involved in nociceptive signaling in said cell.For instance, abnormally high proteasome activity has been linked tostrong deficits of neuronal plasticity (i.e., a major cellular featureof pain). In certain embodiments, modulation comprises activation of aninhibitor of nociceptive signaling.

In still other embodiments, the composition of the present invention canbe used for modulating a protein involved in nociceptive signaling in acell by contacting the cell with the composition of an oligonucleotidedecoy, e.g., an oligonucleotide decoy comprising one or more EGR1binding sites and an agent. In certain embodiments, modulation ofprotein degradation comprises stimulating proteosome function. Incertain embodiments, the protein is involved in nociceptive signaling.Proteins involved in nociceptive signaling include, but are not limitedto membrane proteins (e.g., ion channels, membrane receptors, etc.),soluble signaling molecules (e.g., intracellular signaling molecules orneurotransmitters), synthetic enzymes (e.g., neurotransmitter synthesisenzymes), and transcription factors. Specific examples of such proteinsinclude, but are not limited to, BDKRB2, HTR3A, SCN9A, BDNF, GRM5, NOS1,GCH1,

As used herein, the term “effective” (e.g., “an effective amount”) meansadequate to accomplish a desired, expected, or intended result. Aneffective amount can be a therapeutically effective amount. A“therapeutically effective amount” refers to the amount of an activeingredient that, when administered to a subject, is sufficient to effectsuch treatment of a particular disease or condition. The“therapeutically effective amount” will vary depending on the activeingredient, the disease or condition, the severity of the disease orcondition, and the age, weight, etc., of the subject to be treated.

In certain embodiments, one or more active ingredients, such asoligonucleotide decoys, optionally in a composition (e.g., apharmaceutical composition) comprising an in vivo stabilizing amount ofan agent, are provided in a kit. In certain embodiments, the kitincludes an instruction, e.g., for using said one or more activeingredients or the composition comprising the active ingredients. Incertain embodiments, said instruction describes one or more of themethods of the present invention, e.g., a method for preventing ortreating pain, a method of modulating gene expression in a cell, amethod for modulating nociceptive signaling in a cell, a method formodulating protein degradation in a cell, etc. In certain embodiments,the active ingredients optionally in a composition (e.g., apharmaceutical composition) are provided in a kit are provided inlyophilized form. In certain related embodiments, a kit that comprisesone or more lyophilized components further comprises a solution (e.g., apharmaceutically acceptable saline solution) that can be used toresuspend said one or more of the active ingredients and optional agent.

In general, compositions of the present invention can be administered byany convenient route, for example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.), or orally. Administrationcan be systemic or local. Various delivery systems are known, including,e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., that can be used for administration purposes. Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural/peridural, oral, sublingual, intranasal, intracerebral,intravaginal, transdermal, rectally, by inhalation or topically,particularly to the ears, nose, eyes, or skin. In certain embodiments,more than one active ingredient is administered to a patient in acomposition comprising an agent, and optionally more than one agent. Thepreferred mode of administration is left to the discretion of thepractitioner, and will depend in-part upon the site of the medicalcondition.

In specific embodiments, it may be desirable to administer one or morecompositions locally to the area in need of treatment. This can beachieved, for example, and not by way of limitation, by local infusionduring surgery, topical application (e.g., in conjunction with a wounddressing after surgery), by injection, by means of a catheter, by meansof a suppository, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. In some embodiments, administration canbe by direct injection at the site (e.g., former, current, or expectedsite) of pain.

In certain embodiments, it may be desirable to introduce one or morecompositions into the nervous system by any suitable route, includingbut not restricted to intraventricular, intrathecal, perineural orepidural/peridural injection. Intraventricular injection can befacilitated by an intraventricular catheter, for example, attached to areservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant.

A dose can be administered and then repeated as needed as determined bythose of ordinary skill in the art. Thus, in some embodiments, a singledose is contemplated. In other embodiments, two or more doses arecontemplated. Where more than one dose is administered to a subject, thetime interval between doses can be any time interval as determined bythose of ordinary skill in the art. For example, the time intervalbetween doses can be about 1 hour to about 2 hours, about 2 hours toabout 6 hours, about 6 hours to about 10 hours, about 10 hours to about24 hours, about 1 day to about 2 days, about 1 week to about 2 weeks, orlonger, or any time interval derivable within any of these recitedranges. Dosage forms can, for example, be adapted to be administered toa patient no more than a certain number per day, such as no more thantwice per day, or only once per day. Dosing can be provided alone or incombination with other drugs and can continue as long as required foreffective treatment or prevention, such as effective treatment orprevention of pain.

Combination Therapy

In certain embodiments, compositions of the present invention can beused in combination therapy with at least one other therapeutic agent.The other therapeutic can be another composition comprising an activeingredient. The active ingredient/agent composition and the therapeuticagent can act additively or synergistically. In some embodiments,administration of both the active ingredient/agent composition and thetherapeutic agent is concurrent. In other embodiments, an activeingredient/agent composition is administered prior or subsequent toadministration of another therapeutic agent.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which the present application belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present application,representative methods and materials are herein described.

Following long-standing patent law convention, the terms “a”, “an”, and“the” refer to “one or more” when used in this application, includingthe claims. Thus, for example, reference to “a carrier” includesmixtures of one or more carriers, two or more carriers, and the like.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive. It is specifically contemplated that any listingof items using the term “or” means that any of those listed items mayalso be specifically excluded from the related embodiment.

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

EXAMPLES Example 1 Clinical Response Score of OligonucleotideFormulations

A method was developed to identify the appropriate amount of calcium toadd to a formulation in order to prevent clinical signs and adverseevents following the intrathecal delivery of an oligonucleotide.

Briefly, rats were anesthetized using isoflurane, injected intrathecally(percutaneous delivery, L5/6, 0.02 mL), placed in a cage to recover andtheir behavior was recorded for ˜60 min. Using a saline+oligonucleotideformulation (double stranded, 23 base pairs, molecular weight=14092.92g/mol, % GC=69.5%, sense strand: 5′-GTATGCGTGGGCGGTGGGCGTAG-3′),thirteen spontaneous or evoked clinical signs that can occur followingthe delivery of an oligonucleotide were identified: tail shaking, tailstiffness, tail wagging, hunched back, vocalization, agitation, freezingbehavior, distress/seizure, rear/hindpaw motor dysfunction, exaggeratedvocalization following tail pinch, exaggerated escape following tailpinch, induced wagging/stiffness following tail pinch. The presence orabsence of a sign during the observation period was numerically recordedby 1 or 0, respectively. The performance of a formulation to prevent theoccurrence of those signs was judged based on its total numerical scoreout of 13 and was compared to the score of a control, saline intrathecalinjection.

A screening method was developed in rats to determine the appropriatemolar ratio of CaCl₂ (dihydrate CaCl₂.2H₂O, molecular weight=147.02g/mol) relative to the oligonucleotide that eliminated these effects.Briefly, rats were lightly anesthetized in order to perform apercutaneous lumbar IT injection of the oligonucleotide formulation (100mg/mL, 0.02 mL). After the injection, animals were allowed to recoverfrom anesthesia and placed in a cage. Clinical signs were observed forapproximately 1 h and a clinical score based on the occurrence ofpredetermined clinical signs was calculated. In an iterative manner,several formulations of the oligonucleotide that contained weight ratiosof oligonucleotide: CaCl₂ ranging from 1:0.002 gram (molar ratio of1:0.2) to 1:0.026 gram (molar ratio of 1:2.64) were tested. Resultsindicated that clinical signs were eliminated starting at a weight ratioof oligonucleotide:CaCl₂ of 1:0.0146 gram (molar ratio of 1:1.4 M). Theeffect was maintained up to the highest tested ratio. Based on theseresults, a fixed weight ratio of oligonucleotide: CaCl₂ of1:0.0198±0.003 (molar ratio of 1:1.8±0.3 M) was determined to be optimalfor preventing clinical signs that can occur upon the administration ofan oligonucleotide into the CSF (FIG. 1). Further experiments showedthat injecting a single strand oligonucleotide produced the sameclinical reactions compared to a double-stranded one, confirming aclass-effect for nucleotide-based compounds (FIG. 1).

Example 2 Characterizing an Oligonucleotide:Calcium Binding Relationship

Experiments were conducted to characterize a oligonucleotide:calciumbinding relationship. Particular efforts were dedicated to characterizethe amount of calcium remaining free, unbound to the oligonucleotide ofExample 1 since the concentration of calcium that is introduced in theformulation, depending on the oligonucleotide concentration, can exceedthe endogenous CSF calcium concentration. A broad range of formulationscontaining 1.4 to 250 fold excess of calcium relative to theoligonucleotide concentration were prepared and free calcium measured(FIG. 2).

Results showed that the quantity of calcium that binds theoligonucleotide follows a linear relationship (R²=0.89) that increaseswith the excess of CaCl₂. The more calcium is added, the more is boundto the oligonucleotide until a plateau of binding saturation is reached.The binding was also influenced by the overall ionic strength of thetested solution, which was modulated by adding NaCl: the higher theionic strength, the higher the calcium binding (FIG. 2). Altogether,this set of results indicated that only a small portion of the calciumremains free in presence of the oligonucleotide in the formulation. Dueto technical constraints linked to calcium detection assay, initialexperiments were conducted with low concentrations of oligonucleotides(0.1-3 mM). Complementary techniques allowing the testing ofexperimental conditions with higher oligonucleotide concentrationsconfirmed that up to the oligonucleotide solubility limit (13.5 mM), theamount of calcium that remained free was minimal relative to theconcentration initially introduced in the formulation and within rangeof the endogenous CSF concentration (FIG. 3).

Collectively, these data show that at the definedoligonucleotide:calcium ratio, the calcium introduced in the formulationadequately saturates the calcium binding sites present on theoligonucleotide to prevent the buffering the CSF calcium. Further, theydemonstrate that the formulation does not present potential toxicity interms of artificially introducing a high calcium concentration in theCSF.

Example 3 Pharmacological Analysis of an Oligonucleotide Formulation

Complementary experiments were conducted to ensure that the presence ofcalcium in the formulation of Example 1 did not alter thepharmacological properties of the oligonucleotide. The testedoligonucleotide is a transcription factor decoy inhibiting thetranscription factor EGR1 and prevents the development of pain followinginjury. Competition ELISA experiments showed that calcium, even at ahigh excess of concentration, did not impact the affinity of theoligonucleotide for EGR1 (FIG. 4A) nor its stability (FIG. 4B).Behavioral testing of the oligonucleotide in the incisional model andthe spared nerve injury preclinical models of pain showed similarefficacy with formulations in presence or absence of calcium (FIG. 5).

Example 4 Long-Term Stability Study of an Oligonucleotide Formulation

Following the determination of the optimal oligonucleotide:calcium ratioregarding the oligonucleotide of Example 1, experiments were conductedto further develop a suitable formulation that would provide adequatelong-term stability of an oligonucleotide/calcium containing liquidsolution. Initial experiments evaluated the need for a buffering agentby preparing oligonucleotide/calcium solutions in water, asoligonucleotides are known to contain a certain amount of bufferingcapacity. After adjusting the pH to ˜7.5, the pH of the solution wasevaluated over a 2 week period. pH was not maintained and pH “drift” wasnoted in the solution (Table 1). Therefore, further experiments wereconducted to select an appropriate buffer that would provide adequate pHcontrol and also be compatible with the proposed route of administration(intrathecal). Sodium phosphate was the initial choice of buffer,however experiments indicated compatibility issues with the compound.Low concentrations of sodium phosphate (<5 mM) did not provide adequatebuffering capacity to maintain pH, while higher concentrations (≥5mM)resulted in visible precipitation, presumably due to the formation ofcalcium phosphate (Table 2). Therefore Tromethamine (Tris), which doesnot contain phosphates, was evaluated for compatibility and bufferingcapacity. Experiments indicated that 10 mM Tromethamine (Tris) providedadequate pH control (stable at pH 7.5) and no compatibility issues wereobserved with the oligonucleotide:calcium containing solution (Table 3).

TABLE 1 Stability of the oligonucleotide: calcium formulation in absenceof buffer Oligonucleotide Concentration, mg/mL pH Time RefrigeratorFreezer Refrigerator Freezer Interval (5° C.) (-20° C.) (5° C.) (−20°C.) Day 0 7.47 7.5 Day 3 47.7 46.8 8.28 7.58 190 186.8 8.02 7.61 Day 744 46.3 7.9 7.67 192 187.6 7.85 7.61 Day 10 47.1 46.7 193.8 193.8

Oligonucleotide was formulated with calcium chloride in H₂O at a1:0.0155 weight ratio (1:1.55 molar ratio) and the pH was adjusted to7.5 with small amount of diluted sodium hydroxide and dilutedhydrochloric acid. The study was performed with ˜190 mg/mL and ˜50 mg/mLoligonucleotide concentrations at two different storage temperatures of5° C. and −20° C. The concentration of total oligonucleotide and pH ofthe AYX1 formulation were monitored for a period of 10 days.

TABLE 2 Stability of the oligonucleotide:calcium formulation with sodiumphosphate buffer Oligonucleotide Day 0 Results Day 3 Results Day 7Results Day 14 Results Formulation Visual pH Visual pH Visual pH VisualpH 1:0.001 CaCl₂, no Clear, 7.555 Clear, 7.434 Clear, 7.41 Clear, 7.328sodium phosphate Colorless Colorless Colorless Colorless buffer, 4.5mg/mL of NaCl, Total volume: 1.325 mL² 1:0.001 CaCl₂, 2.5 Clear, 7.491Clear, 7.47 Clear, 7.457 Clear, 7.415 mM sodium Colorless ColorlessColorless Colorless phosphate buffer, 4.5 mg/mL of NaCl, Total volume:1.25 mL 1:0.001 CaCl₂, 5.0 Clear, 7.466 Clear, 7.466 Clear, 7.454 Clear,7.393 mM sodium Colorless Colorless Colorless Colorless phosphatebuffer, 4.5 mg/mL of NaCl, Total volume: 1.25 mL 1:0.002 CaCl₂, noClear, 7.498 Clear, 7.317 Clear, 7.281 Clear, 7.209 sodium phosphateColorless Colorless Colorless Colorless buffer, 4.5 mg/mL of NaCl, Totalvolume: 1.25 mL 1:0.002 CaCl₂, 2.5 Clear, 7.546 Clear, 7.521 Clear,7.478 Clear, 7.421 mM sodium Colorless Colorless Colorless Colorlessphosphate buffer, 4.5 mg/mL of NaCl, Total volume: 1.25 mL 1:0.002CaCl_(2,) 5.0 Clear, 7.508 Slightly 6.743 Slightly 6.724 Slightly 6.654mM sodium Colorless turbid turbid turbid phosphate buffer, 4.5 mg/mL ofNaCl, Total volume: 1.25 mL

Oligonucleotide (112 mg/mL, 7.95 mM) was formulated with calciumchloride in H₂O at a 1:0.01 or 1:0.02 weight ratio (1:1-1:2 molar ratio)and the pH was adjusted to 7.5 with small amount of diluted sodiumhydroxide and diluted hydrochloric acid. Sodium phosphate was added forbuffering of the formulations and sodium chloride was added as theexcipient to adjust the osmolality of the formulation. Testing wasconducted at the 5° C. storage temperature. The stability and pH of theformulations were monitored for a period of 14 days. Turbidity indicatesprecipitation occurring within the solution.

TABLE 3 Stability of the oligonucleotide: calcium formulation with Trisbuffer A. Fifteen days stability Ion Size Exchange Exclusion HPLC HPLCSample Visual Purity Purity Time Interval Description Inspection pH(Area %) (Area %) Day 0 Drug Product Clear, 7.451 93.39 99.3 colorlessPlacebo Clear, 7.4 NA NA colorless Day 3 Drug Product Clear, 7.522 NA NAcolorless Placebo Clear, 7.439 NA NA colorless Day 7 Drug Product Clear,7.331 NA NA colorless Placebo Clear, 7.546 NA NA colorless Day 14 DrugProduct Clear, 7.484 93.53 99.2 colorless Placebo Clear, 7.367 NA NAcolorless B. Three months stability Test Method T = 0 T = 1 month T = 2month T = 3 month Visual-Color Colorless Colorless Colorless ColorlessVisual-Clarity Clear Clear Clear Clear Visual-Appearance Free fromvisible Free from visible Free from Free from particulates particulatesvisible visible particulates particulates Total 111.8 mg/mL 111.9 mg/mL111.4 mg/mL 108.4 mg/mL Oligonucleotide Content Purity by SEC- HPLC a.Oligonucleotide 99.30% 99.20% 99.20% 99.20% Main Peak b. Single StrandRRT % area RRT % area RRT RRT Impurities 0.88  0.61% 0.88 0.59% % area %area c. Unspecified 1.13  0.12% 1.13 0.20% 0.88 0.88 Impurities 0.63%0.63% 1.14 1.13 0.21% 0.13% Purity by IEX- HPLC a. Oligonucleotide 93.6%Total 93.7% Total 92.9% Total 91.3% Total Main Peaks 59.6% AWL 49.9% AWL49.3% AWL 48.8% AWL 44.0% AWM 43.8% AWM 43.6% AWM 42.5% AWM b.impurities % Area % Area % Area % Area  2.32%  2.74%  2.50%  3.12% 0.68%  1.14%  0.91%  0.70% % Area % Area % Area % Area  0.30%  0.27% 0.31%  0.31%  1.79%  1.53%  1.79%  2.88%  0.73%  0.27%  0.61%  0.98% pH7.5 7.5 7.5 7.6

Stability of the oligonucleotide:calcium formulation buffered with Tris.Table 3A: Oligonucleotide (112 mg/mL, 7.95 mM) was formulated withcalcium chloride in H₂O at a 1:0.02 weight ratio (1:2 molar ratio) andthe pH was adjusted to 7.5 with small amount of diluted sodium hydroxideand diluted hydrochloric acid. Tris (10 mM final concentration) wasadded for buffering of the formulation and sodium chloride was added asthe excipient to adjust the osmolality of the formulation. Testing wasconducted at the 5° C. storage temperature. The stability and pH of theformulations were monitored for a period of 14 days. Additional measuresof oligonucleotide stability and integrity (Ion Exchange HPLC purity andSize Exclusion HPLC) were performed at time zero and at 14 days. Table3B: long term stability of the oligonucleotide: calcium formulation.Oligonucleotide (110 mg/mL, 7.8 mM) was formulated with calcium chloridein H₂O at a 1:0.018 weight ratio (1:1.8 molar ratio), the pH wasadjusted to 7.5 and Tris added (10 mM final concentration) pH,precipitation (visual observation) and oligonucleotide integrity (sizeexclusion SEC-HPLC, Ion exchange IEX-HPLC) were measured for 3 months.Three storage conditions were tested: 5° C., 25° C. and 40° C., withsimilar results. The outcome of the 5° C. storage condition is shown.

It will be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of this disclosure. Accordingly, the present embodiments areto be considered as illustrative and not restrictive, and the inventionis not to be limited to the details given herein, but may be modifiedwithin the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by referencein their entirety.

What is claimed is:
 1. A pharmaceutical composition comprising an activeingredient and an in vivo stabilizing amount of an agent, wherein theagent is associated with an adverse effect in vivo caused by theadministration of the active ingredient without the agent, and whereinthe in vivo stabilizing amount is the amount that substantiallysaturates the binding sites of the active ingredient to the agent. 2.The pharmaceutical composition of claim 1, wherein the active ingredientis selected from the group consisting of a nucleic acid, a peptide, anda small organic molecule, or a combination thereof.
 3. Thepharmaceutical composition of claim 1, wherein the active ingredient isan oligonucleotide decoy.
 4. The pharmaceutical composition of claim 1,wherein the active ingredient is a nucleic acid comprising one or moretranscription factor binding sites.
 5. The pharmaceutical composition ofclaim 1, wherein the active ingredient is an oligonucleotide decoyuseful for the treatment of pain or modulation of nociceptive signaling.6. The pharmaceutical composition of claim 1, wherein the activeingredient is a nucleic acid comprising SEQ ID NOs: 1-40, 42, 45, 47-52,or
 53. 7. The pharmaceutical composition of claim 1, wherein the agentis an ion, a protein, a carbohydrate, an alcohol, a lipid, or a vitamin.8. The pharmaceutical composition of claim 1, wherein the agent isassociated with an adverse effect caused by the administration of theactive ingredient to the nervous system.
 9. The pharmaceuticalcomposition of claim 8, wherein the agent is associated with an adverseeffect caused by the administration of the active ingredient without theagent in CSF, neuronal parenchyma, or conjunctive tissue.
 10. Thepharmaceutical composition of claim 8, wherein administration is byinjection.
 11. The pharmaceutical composition of claim 9, wherein theagent is a cation or a vitamin.
 12. The pharmaceutical composition ofclaim 11, wherein the cation is a calcium ion, a magnesium ion, or apotassium ion.
 13. The pharmaceutical composition of claim 11, whereinthe cation is a metal ion.
 14. The pharmaceutical composition of claim1, wherein the agent is associated with an adverse effect caused by theadministration of the active ingredient without the agent in blood. 15.The pharmaceutical composition of claim 14, wherein the agent is acation or a vitamin.
 16. The pharmaceutical composition of claim 15,wherein the cation is a calcium ion, a magnesium ion, or a potassiumion.
 17. The pharmaceutical composition of claim 15, wherein the cationis a metal ion.
 18. The pharmaceutical composition of claim 1, whereinthe resulting free agent amount within the pharmaceutical composition isat a level less than a predetermined level.
 19. The pharmaceuticalcomposition of claim 1, wherein the resulting free agent amount withinthe pharmaceutical composition is at a level greater than apredetermined level.
 20. The pharmaceutical composition of claim 18,wherein the predetermined level is the endogenous level of the agent.21. The pharmaceutical composition of claim 1, wherein the activeingredient is a nucleic acid and the agent is calcium ion and whereinthe pharmaceutical composition is formulated for intrathecaladministration.
 22. The pharmaceutical composition of claim 1, whereinthe active ingredient is an oligonucleotide decoy and the agent iscalcium ion and wherein the pharmaceutical composition is formulated forintrathecal administration.
 23. The pharmaceutical composition of claim1, wherein the molar ratio or the weight ratio of the active ingredientto the agent ranges from about 1:1000 to about 1000:1.
 24. Thepharmaceutical composition of claim 1, wherein the active ingredient isa nucleic acid and the agent is calcium ion as comprised in calciumchloride, and wherein the weight ratio of the active ingredient tocalcium chloride is from about 1:1, 2:1, 4:1, 5:1, 15:1, 30:1, 50:1,100:1, 200:1, 250:1, 300:1, 400:1, or 500:1, or any range derivabletherein.
 25. The pharmaceutical composition of claim 1, wherein theactive ingredient is an oligonucleotide decoy and the agent is calciumion as comprised in calcium chloride, and wherein the weight ratio ofthe active ingredient to calcium chloride is from about 1:1, 2:1, 4:1,5:1, 15:1, 30:1, 50:1, 100:1, 200:1, 250:1, 300:1, 400:1, or 500:1, orany range derivable therein.
 26. The pharmaceutical composition of claim1, wherein the active ingredient is an oligonucleotide decoy and theagent is a cation or a vitamin.
 27. The pharmaceutical composition ofclaim 26, wherein the cation is a calcium ion, a magnesium ion, or apotassium ion.
 28. The pharmaceutical composition of claim 26, whereinthe cation is a metal ion.
 29. The pharmaceutical composition of claim 1further comprising a buffer.
 30. The pharmaceutical composition of claim1, wherein the active ingredient is an oligonucleotide decoy, the agentis calcium ion and wherein the pharmaceutical composition furthercomprises a non-phosphate based buffer.
 31. A method of reducing anadverse effect of an active ingredient comprising administering theactive ingredient with an in vivo stabilizing amount of an agent,wherein the agent is associated with the adverse effect of the activeingredient caused by the administration of the active ingredient withoutthe agent, and wherein the in vivo stabilizing amount is the amount thatsubstantially saturates the binding sites of the active ingredient tothe agent.
 32. A method for treating or managing pain in a subjectcomprising administering to the subject the pharmaceutical compositionof claim 1, wherein the active ingredient is an oligonucleotide decoycomprising one or more binding sites for EGR1 and wherein the agent is acalcium ion.